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Inactivation of NF-kappaB by genistein is mediated via Akt signaling pathway in breast cancer cells
Abstract
Genistein, a natural isoflavonoid found in soybean products, has been proposed to be associated with a lower rate of breast cancer in Asian women. Studies from our laboratory and others have shown that genistein can induce apoptosis by regulating the expression of apoptosis-related genes in breast cancer cells. However, the precise molecular mechanism(s) by which genistein induces apoptotic cell death is not clear. In order to investigate such mechanism, we tested the role of Akt and NF-kappaB in genistein-treated MDA-MB-231 breast cancer cells. We found that inhibition of cell growth and induction of apoptosis by genistein are partly mediated through the downregulation of Akt and NF-kappaB pathways. Gel shift assay showed that NF-kappaB DNA-binding activity in MDA-MB-231 cells transfected with Akt cDNA was induced, suggesting that there is a cross-talk between NF-kappaB and Akt signaling pathway. Moreover, we found that genistein could abrogate EGF and Akt induced NF-kappaB activation. From these results, we conclude that the inactivation of NF-kappaB by genistein in MDA-MB-231 breast cancer cells is partly mediated via Akt pathway, which could be useful for rational design of strategies for the prevention and/or treatment of breast cancer.
... Apoptosis induced by Fas/FasL apoptosis signaling pathwayWang et al. (2020) Induces apoptosis and inhibits cell division by regulating MEK/ERK 1/2, and PI3K/ Akt pathwaysRice and Whitehead (2014),Kaushik et al. (2018) Up-regulates the expression/activity of Cyclin D1, p21, p27, p53, p53 and induced cell cycle arrestSakamoto et al. (2010) Triggers apoptosis by regulating p53/Bax/Bcl-2 signaling pathwayLi et al. (1999) Genistein Inhibit DNMT1 and expression of hTERT, reduces estrogenic stimulation in breast cancerGong et al. (2003) Suppress ER-dependent signal transduction Inhibit ERα mRNA and protein expressionLee et al. (2014) Induce downregulation of E2F1 and CIP2A in breast cancer cell lines, that correlates with growth inhibition and apoptosisZhao et al. (2016) Suppress cell proliferation by the inhibition of PI3K/Akt-NF-kB pathwayLi et al. (1999),Gong et al. (2003) Induce differentiation on mammospheres by regulating PI3K/Akt and MEK/ERK signaling pathwaysLiu et al. (2016) ...
... Apoptosis induced by Fas/FasL apoptosis signaling pathwayWang et al. (2020) Induces apoptosis and inhibits cell division by regulating MEK/ERK 1/2, and PI3K/ Akt pathwaysRice and Whitehead (2014),Kaushik et al. (2018) Up-regulates the expression/activity of Cyclin D1, p21, p27, p53, p53 and induced cell cycle arrestSakamoto et al. (2010) Triggers apoptosis by regulating p53/Bax/Bcl-2 signaling pathwayLi et al. (1999) Genistein Inhibit DNMT1 and expression of hTERT, reduces estrogenic stimulation in breast cancerGong et al. (2003) Suppress ER-dependent signal transduction Inhibit ERα mRNA and protein expressionLee et al. (2014) Induce downregulation of E2F1 and CIP2A in breast cancer cell lines, that correlates with growth inhibition and apoptosisZhao et al. (2016) Suppress cell proliferation by the inhibition of PI3K/Akt-NF-kB pathwayLi et al. (1999),Gong et al. (2003) Induce differentiation on mammospheres by regulating PI3K/Akt and MEK/ERK signaling pathwaysLiu et al. (2016) ...
... Gong et al. (2003) Inhibits cyclin D1 expression and induces cell cycle arrestRahal and Simmen (2010) 8-Prenylnaringenin Suppresses estrogen-signaling through the inhibition of BIG3-PHB2 interactions Yang et al. (2019) modulates the MAPK signaling pathway Brunelli et al. (2007) Resveratrol Inhibits CYP-1A1/1A2/1B1 and 2E1 Mikstacka et al. (2007) Decreases the action of NF-kB Mikstacka et al. (2007) Downregulates expression of Cyclin D1, p21, p27, p53, Bax/Bcl-2 Inhibits of MEK/ERK, PI3eK/Akt signaling pathways Limer and Speirs (2004) Inhibit expression of Bcl-2, and promote apoptosis Nguyen et al. (2008) Pterostilbene Increase Caspase 3/7, caspase 3, GP X Bax and P53 activity.Decreases Bcl-2, Akt and MMP Causes prolongation of S-phase; Inhibit the activity of CYP-1A1/1A2/1B1 and 2E1 Suh et al. (2007) Decrease the activation of NF-kB Mikstacka et al. (2007) Coumestrol Promotes senescence through the p53-p21 pathway by inducing ROS production Lee et al. (2013) Sesamin Tumor supression via downregulating the expression of EGFR and MAPK Majdalawieha et al. mitotic phase arrest in breast cancer cells causes 60% reduction in cancer cells Abarzua et al. (2012) ...
Phytoestrogens are non-steroidal, polyphenolic compounds that are derived from plants and have biological properties similar to those of human estrogens. Their bioactivity, which is based on the core ring system, is caused by their structural resemblance to estrogen. Flavonoids, coumestans, lignans, and stilbenes are the four major categories into which they can be divided. They are structurally and functionally related to ovarian and placental estrogens, which are essential in female reproductive processes. Phytoestrogens are present in numerous dietary supplements and find application in hormone replacement therapy as an alternative to synthetic hormones. In addition, they provide health benefits for osteoporosis, heart disease, breast cancer, and prostate cancer. There is a growing interest in using phytoestrogen as preventative medicine in the form of nutraceuticals. This literature provides comprehensive information about the types, sources, and biological actions of phytoestrogens in the reproductive system.
... The EGFR/Akt/NFκB pathway modulation play a role in cell differentiation [58], which leads to cancer cell death. With genistein, the activity of Akt is suppressed, promoting the deactivation of downstream signaling pathways, including NF-κB [2,59]. This was demonstrated by the electrophoretic mobility shift assay in MDA-MB-231 cells, along with inhibition in the activation of Akt by preventing EGF signal triggering [59]. ...
... With genistein, the activity of Akt is suppressed, promoting the deactivation of downstream signaling pathways, including NF-κB [2,59]. This was demonstrated by the electrophoretic mobility shift assay in MDA-MB-231 cells, along with inhibition in the activation of Akt by preventing EGF signal triggering [59]. Furthermore, through modulating AMPK and COX-2, the combination of genistein and capsaicin instigated synergistic apoptotic consequences [60]. ...
... The merging of genistein, cisplatin, docetaxel, and doxorubicin has also been shown to cause NF-kB deactivation, resulting in enhanced growth inhibition and finally apoptosis in MDA-MB-231 cells [61]. This is said to be brought about by the MEK5/ERK5 pathway [62], revoking the EGF and Akt induced NF-kappa B activation, which led to the conclusion that the inactivation of NF-kappa B cancer cells is partly arbitrated though the Akt pathway [59]. In silico studies have studied the binding interactions of active sites of these molecules, which confirmed these findings along with revelation that the amino acid residues of lysine, serine, and aspartic acid play a major role [63]. ...
Genistein is an isoflavonoid present in high quantities in soybeans. Possessing a wide range of bioactives, it is being studied extensively for its tumoricidal effects. Investigations into mechanisms of the anti-cancer activity have revealed many pathways including induction of cell proliferation, suppression of tyrosine kinases, regulation of Hedgehog-Gli1 signaling, modulation of epigenetic activities, seizing of cell cycle and Akt and MEK signaling pathways, among others via which the cancer cell proliferation can be controlled. Notwithstanding, the observed activities have been time- and dose-dependent. In addition, genistein has also shown varying results in women depending on the physiological parameters, such as the early or post-menopausal states.
... Genistein directly suppresses the activity of Akt and therefore this substance promotes the inactivation of its downstream signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [5][6][7]. The electrophoretic mobility shift assay further demonstrated that treatment with genistein directly inactivates NF-κB in MDA-MB-231 cells [6]. ...
... Genistein directly suppresses the activity of Akt and therefore this substance promotes the inactivation of its downstream signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [5][6][7]. The electrophoretic mobility shift assay further demonstrated that treatment with genistein directly inactivates NF-κB in MDA-MB-231 cells [6]. Genistein also inhibits Akt activation by preventing its upstream EGF signal activation [6,7]. ...
... The electrophoretic mobility shift assay further demonstrated that treatment with genistein directly inactivates NF-κB in MDA-MB-231 cells [6]. Genistein also inhibits Akt activation by preventing its upstream EGF signal activation [6,7]. It can be concluded that genistein inhibits NF-κB activation either by EGF and Akt inactivation or by directly inactivating it. ...
Cancers are complex diseases orchestrated by a plethora of extrinsic and intrinsic factors. Research spanning over several decades has provided better understanding of complex molecular interactions responsible for the multifaceted nature of cancer. Recent advances in the field of next generation sequencing and functional genomics have brought us closer towards unravelling the complexities of tumor microenvironment (tumor heterogeneity) and deregulated signaling cascades responsible for proliferation and survival of tumor cells. Phytochemicals have begun to emerge as potent beneficial substances aimed to target deregulated signaling pathways. Isoflavonoid genistein is an essential phytochemical involved in regulation of key biological processes including those in different types of cancer. Emerging preclinical evidence have shown its anti-cancer, anti-inflammatory and anti-oxidant properties. Testing of this substance is in various phases of clinical trials. Comprehensive preclinical and clinical trials data is providing insight on genistein as a modulator of various signaling pathways both at transcription and translation levels. In this review we have explained the mechanistic regulation of several key cellular pathways by genistein. We have also addressed in detail various microRNAs regulated by genistein in different types of cancer. Moreover, application of nano-formulations to increase the efficiency of genistein is also discussed. Understanding the pleiotropic potential of genistein to regulate key cellular pathways and development of efficient drug delivery system will bring us a step towards designing better chemotherapeutics.
... [82] Human and animal studies suggest that isoflavones exert their inhibitory effects on carcinogenesis and cancer progression by induction of apoptosis and inhibition of cell proliferation. [132] The induction of apoptosis by isoflavone has been believed to be mediated through the regulation of multiple cell signaling pathways including NF-B, [133] serine/threonine protein kinase B (Akt), [134] mitogen-activated protein kinases (MAPK), [135] wingless (Wnt), [136] Notch, [137] p53, [138] and androgen receptor (AR) [139] signaling pathways. ...
... Soybeans Isoflavones Intake of isoflavones was significantly associated with a reduced risk of lung, stomach, breast and colorectal cancer Isoflavones induce apoptosis and inhibit cell proliferation by regulating signaling pathways including NF-B, Akt, MAPK, Wnt, Notch, p53, and AR to inhibit carcinogenesis and cancer progression. [133][134][135][136][137][138][139] Ginger Curcumin Curcumin has been shown to regulate multiple cell signaling pathways simultaneously to mitigate or prevent many different types of cancer, including multiple myeloma and colorectal, pancreatic, breast, prostate, lung, head and neck cancers. ...
The incidence rate of cancer is increasing year by year due to the aging of the population, unhealthy living, and eating habits. At present, surgery and medication are still the main treatments for cancer, without paying attention to the impact of individual differences in health management on cancer. However, increasing evidence suggests that individual psychological status, dietary habits, and exercise frequency are closely related to the risk and prognosis of cancer. The reminder to humanity is that the medical concept of the unified treatment plan is insufficient in cancer treatment, and a personalized treatment plan may become a breakthrough point. On this basis, the concept of “Humanistic Health Management” (HHM) is proposed. This concept is a healthcare plan that focuses on self‐health management, providing an accurate and comprehensive evaluation of individual lifestyle habits, psychology, and health status, and developing personalized and targeted comprehensive cancer prevention and treatment plans. This review will provide a detailed explanation of the relationship between psychological status, dietary, and exercise habits, and the regulatory mechanisms of cancer. Intended to emphasize the importance of HHM concept in cancer prevention and better prognostic efficacy, providing new ideas for the new generation of cancer treatment.
... AKT1 and TNFα promote the phosphorylation and degradation of IκB, resulting in the release and nuclear translocation of NF-κB [60], which in turn binds to specific deoxyribonucleic acid (DNA) sequences to regulate the transcription of pro-inflammatory proteins, including TNFα and IL6 [59]. Conversely, the inhibition of AKT1 or TNFα maintains NF-κB-IκB association, thus repressing NASH inflammation [61,62]. Therefore, the antiinflammatory feature of Aloe vera may be the combined effect of multiple targets. ...
... AKT1 and TNFα promote the phosphorylation and degradation of IκB, resulting in the release and nuclear translocation of NF-κB [60], which in turn binds to specific deoxyribonucleic acid (DNA) sequences to regulate the transcription of pro-inflammatory proteins, including TNFα and IL6 [59]. Conversely, the inhibition of AKT1 or TNFα maintains NF-κB-IκB association, thus repressing NASH inflammation [61,62]. Therefore, the anti-inflammatory feature of Aloe vera may be the combined effect of multiple targets. ...
Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease with limited treatment options. The widely distributed plant Aloe vera has shown protective effects against NASH in animals, yet the precise mechanism remains unknown. In this study, we investigated the potential mechanisms underlying the anti-NASH effects of Aloe vera using a network pharmacology and molecular docking approach. By searching online databases and analyzing the Gene Expression Omnibus dataset, we obtained 260 Aloe vera–NASH common targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the common targets were strongly associated with the key pathological processes implicated in NASH, including lipid and glucose metabolism, inflammation, apoptosis, oxidative stress, and liver fibrosis. Four core proteins, AKT serine/threonine kinase 1 (AKT1), tumor necrosis factor alpha (TNFα), transcription factor c-Jun, and tumor suppressor protein p53, were identified from compound–target–pathway and protein–protein interaction networks. Molecular docking analysis verified that the active ingredients of Aloe vera were able to interact with the core proteins, especially AKT1 and TNFα. The results demonstrate the multi-compound, multi-target, and multi-pathway mechanisms of Aloe vera against NASH. Our study has shown the scientific basis for further experiments in terms of the mechanism to develop Aloe vera-based natural products as complementary treatments for NASH. Furthermore, it identifies novel drug candidates based on the structures of Aloe vera’s active compounds.
... Epidemiological studies have shown that the intake of dietary-rich isoflavones reduced the risk of various human cancers. Genistein works against a number of cancers such as esophagus, colon, prostate, liver, lung, ovarian, bladder, brain, gastric, neuroblastoma, and breast [530][531][532][533][534] . It is also reported to tackle oxidative insult by ischemic-reperfusion via inhibiting XO and COX-2, ascertaining its role as an anti-gout agent [ 367 , 368 ]. ...
... The anticancer mechanism of this compound in SK-OV-3 ovarian and HGC-27 gastric cancer cells is also associated with G2/M phase cell cycle arrest [ 543 , 544 ]. In MDA-MB-231 cells, genistein performed inhibitory cell growth activity by suppressing EGF and Akt mediated NF-κB signaling [532] . Human colorectal cancer cells metastasis was abolished by genistein via Fms related tyrosine kinase 4 (FLT4) suppression, a metastatic disease marker [545] . ...
Gout is an inflammatory disease caused by metabolic disorder or genetic inheritance. People throughout the world are strongly dependent on ethnomedicine for the treatment of gout and some receive satisfactory curative treatment. The natural remedies as well as established drugs derived from natural sources or synthetically made exert their action by mechanisms that are closely associated with anticancer treatment mechanisms regarding inhibition
of xanthine oxidase, feedback inhibition of de novo purine synthesis, depolymerization and disappearance of microtubule, inhibition of NF-ĸB activation, induction of TRAIL, promotion of apoptosis, and caspase activation and proteasome inhibition. Some anti-gout and anticancer novel compounds interact with same receptors for their action, e.g., colchicine and colchicine analogues. Dietary flavonoids, i.e., chrysin, kaempferol, quercetin, fisetin, pelargonidin,
apigenin, luteolin, myricetin, isorhamnetin, phloretinetc etc. have comparable IC50 values with established anti-gout drug and effective against both cancer and gout. Moreover, a noticeable number of newer anticancer compounds have already been isolated from plants that have been using by local traditional healers and herbal practitioners to treat gout. Therefore, the anti-gout plants might have greater potentiality to become selective candidates for screening
of newer anticancer leads
... Furthermore, 1-10 µg/mL of GNT suppressed angiogenesis and cell mutation by decreasing tyrosine kinase, ribosomal S6 kinases, and DNA topoisomerases I and II [97], while at a 50 µM concentration, it decreased angiogenesis and inhibited cell division through the underlying mechanism of downregulating COX, topoisomerase II enzyme TPA, and EROD protein activity [96]. Followed by angiogenesis, GNT (15-30 µM) [112] and (5-20 µM) [24] obstructed cancer cell migration and invasion, respectively, by lowering levels of CDKs, tyrosine kinase, and paracrine stimulation and decreasing MEK5, ERK5, phospho-ERK5, NF-κB/p65, and Bcl-2/Bax. ...
... Cappelletti et al. revealed that GNT (15-30 µM) inhibits metastasis by lowering levels of CDKs, tyrosine kinase, DNA topoisomerase II, and paracrine stimulation in the BT20 cell line [112]. An early study showed that GNT (1-10 µg/mL) obstructed angiogenesis and cell mutation by decreasing the expression of ribosomal S6 kinases and tyrosine kinase [97]. ...
Citation: Sohel, M.; Biswas, P.; Al Amin, M.; Hossain, M.A.; Sultana, H.; Dey, D.; Aktar, S.; Setu, A.; Khan, M.S.; Paul, P.; et al. Genistein, a Potential Phytochemical against Breast Cancer Treatment-Insight into the Molecular Mechanisms. Processes 2022, 10, 415. https://doi.
... Epidemiological studies have shown that the intake of dietary-rich isoflavones reduced the risk of various human cancers. Genistein works against a number of cancers such as esophagus, colon, prostate, liver, lung, ovarian, bladder, brain, gastric, neuroblastoma, and breast [530][531][532][533][534] . It is also reported to tackle oxidative insult by ischemic-reperfusion via inhibiting XO and COX-2, ascertaining its role as an anti-gout agent [ 367 , 368 ]. ...
... The anticancer mechanism of this compound in SK-OV-3 ovarian and HGC-27 gastric cancer cells is also associated with G2/M phase cell cycle arrest [ 543 , 544 ]. In MDA-MB-231 cells, genistein performed inhibitory cell growth activity by suppressing EGF and Akt mediated NF-κB signaling [532] . Human colorectal cancer cells metastasis was abolished by genistein via Fms related tyrosine kinase 4 (FLT4) suppression, a metastatic disease marker [545] . ...
Gout is an inflammatory disease caused by metabolic disorder or genetic inheritance. People throughout the world are strongly dependent on ethnomedicine for the treatment of gout and some receive satisfactory curative treatment. The natural remedies as well as established drugs derived from natural sources or synthetically made exert their action by mechanisms that are closely associated with anticancer treatment mechanisms regarding inhibition of xanthine oxidase (XO), feedback inhibition of de novo purine synthesis, depolymerization and disappearance of microtubule, inhibition of NFĸB activation, induction of TRAIL, promotion of apoptosis, and caspase activation and proteasome inhibition. Some anti-gout and anticancer novel compounds interact with same receptors for their action e.g., colchicine and colchicine analogues. Dietary flavonoids i.e. chrysin, kaempferol, quercetin, fisetin, pelargonidin, apigenin, luteolin, myricetin, isorhamnetin, phloretinetc etc. have comparable IC50 values with established anti-gout drug and effective against both cancer and gout. Moreover, a noticeable number of newer anticancer compounds have already been isolated from plants that have been using by local traditional healers and herbal practitioners to treat gout. Therefore, the anti-gout plants might have greater potentiality to become selective candidate for screening of newer anticancer leads.
... Furthermore, 1-10 µg/mL of GNT suppressed angiogenesis and cell mutation by decreasing tyrosine kinase, ribosomal S6 kinases, and DNA topoisomerases I and II [97], while at a 50 µM concentration, it decreased angiogenesis and inhibited cell division through the underlying mechanism of downregulating COX, topoisomerase II enzyme TPA, and EROD protein activity [96]. Followed by angiogenesis, GNT (15-30 µM) [112] and (5-20 µM) [24] obstructed cancer cell migration and invasion, respectively, by lowering levels of CDKs, tyrosine kinase, and paracrine stimulation and decreasing MEK5, ERK5, phospho-ERK5, NF-κB/p65, and Bcl-2/Bax. ...
... Cappelletti et al. revealed that GNT (15-30 µM) inhibits metastasis by lowering levels of CDKs, tyrosine kinase, DNA topoisomerase II, and paracrine stimulation in the BT20 cell line [112]. An early study showed that GNT (1-10 µg/mL) obstructed angiogenesis and cell mutation by decreasing the expression of ribosomal S6 kinases and tyrosine kinase [97]. ...
... Furthermore, 1-10 µg/mL of GNT suppressed angiogenesis and cell mutation by decreasing tyrosine kinase, ribosomal S6 kinases, and DNA topoisomerases I and II [97], while at a 50 µM concentration, it decreased angiogenesis and inhibited cell division through the underlying mechanism of downregulating COX, topoisomerase II enzyme TPA, and EROD protein activity [96]. Followed by angiogenesis, GNT (15-30 µM) [112] and (5-20 µM) [24] obstructed cancer cell migration and invasion, respectively, by lowering levels of CDKs, tyrosine kinase, and paracrine stimulation and decreasing MEK5, ERK5, phospho-ERK5, NF-κB/p65, and Bcl-2/Bax. ...
... Cappelletti et al. revealed that GNT (15-30 µM) inhibits metastasis by lowering levels of CDKs, tyrosine kinase, DNA topoisomerase II, and paracrine stimulation in the BT20 cell line [112]. An early study showed that GNT (1-10 µg/mL) obstructed angiogenesis and cell mutation by decreasing the expression of ribosomal S6 kinases and tyrosine kinase [97]. ...
Breast cancer (BC) is one of the most common malignancies in women. Although
widespread successful synthetic drugs are available, natural compounds can also be considered as significant anticancer agents for treating BC. Some natural compounds have similar effects as synthetic drugs with fewer side effects on normal cells. Therefore, we aimed to unravel and analyze several molecular mechanisms of genistein (GNT) against BC. GNT is a type of dietary phytoestrogen included in the flavonoid group with a similar structure to estrogen that might provide a strong alternative and complementary medicine to existing chemotherapeutic drugs. Previous research reported that GNT could target the estrogen receptor (ER) human epidermal growth factor receptor-2
(HER2) and several signaling molecules against multiple BC cell lines and sensitize cancer cell lines to this compound when used at an optimal inhibitory concentration. More specifically, GNT mediates the anticancer mechanism through apoptosis induction, arresting the cell cycle, inhibiting angiogenesis and metastasis, mammosphere formation, and targeting and suppressing tumour growth factors. Furthermore, it acts via upregulating tumor suppressor genes and downregulating oncogenes in vitro
and animal model studies. In addition, this phytochemical synergistically reverses the resistance mechanism of standard chemotherapeutic drugs, increasing their efficacy against BC. Overall, in this review, we discuss several molecular interactions of GNT with numerous cellular targets in the BC model and show its anticancer activities alone and synergistically. We conclude that GNT can have favorable therapeutic advantages when standard drugs are not available in the pharma markets.
... Furthermore, 1-10 µg/mL of GNT suppressed angiogenesis and cell mutation by decreasing tyrosine kinase, ribosomal S6 kinases, and DNA topoisomerases I and II [97], while at a 50 µM concentration, it decreased angiogenesis and inhibited cell division through the underlying mechanism of downregulating COX, topoisomerase II enzyme TPA, and EROD protein activity [96]. Followed by angiogenesis, GNT (15-30 µM) [112] and (5-20 µM) [24] obstructed cancer cell migration and invasion, respectively, by lowering levels of CDKs, tyrosine kinase, and paracrine stimulation and decreasing MEK5, ERK5, phospho-ERK5, NF-κB/p65, and Bcl-2/Bax. ...
... Cappelletti et al. revealed that GNT (15-30 µM) inhibits metastasis by lowering levels of CDKs, tyrosine kinase, DNA topoisomerase II, and paracrine stimulation in the BT20 cell line [112]. An early study showed that GNT (1-10 µg/mL) obstructed angiogenesis and cell mutation by decreasing the expression of ribosomal S6 kinases and tyrosine kinase [97]. ...
Breast cancer (BC) is one of the most common malignancies in women. Although widespread successful synthetic drugs are available, natural compounds can also be considered as significant anticancer agents for treating BC. Some natural compounds have similar effects as synthetic drugs with fewer side effects on normal cells. Therefore, we aimed to unravel and analyze several molecular mechanisms of genistein (GNT) against BC. GNT is a type of dietary phytoestrogen included in the flavonoid group with a similar structure to estrogen that might provide a strong alternative and complementary medicine to existing chemotherapeutic drugs. Previous research reported that GNT could target the estrogen receptor (ER) human epidermal growth factor receptor-2 (HER2) and several signaling molecules against multiple BC cell lines and sensitize cancer cell lines to this compound when used at an optimal inhibitory concentration. More specifically, GNT mediates the anticancer mechanism through apoptosis induction, arresting the cell cycle, inhibiting angiogenesis and metastasis, mammosphere formation, and targeting and suppressing tumor growth factors. Furthermore, it acts via upregulating tumor suppressor genes and downregulating oncogenes in vitro and animal model studies. In addition, this phytochemical synergistically reverses the resistance mechanism of standard chemotherapeutic drugs, increasing their efficacy against BC. Overall, in this review, we discuss several molecular interactions of GNT with numerous cellular targets in the BC model and show its anticancer activities alone and synergistically. We conclude that GNT can have favorable therapeutic advantages when standard drugs are not available in the pharma markets.
... Biogenic volatile organic compounds (BVOCs) usually refer to a series of lipophilic small molecules with small molecular weight, low boiling point, and volatility, which are produced by the primary and secondary metabolism of plants (Goff and Klee, 2006). The types of compounds covered by BVOCs are very wide, and different classification methods will result in different generalized compound categories. ...
... The study also confirmed that A. truncatum flavonoids can Ren et al. (2018) 193 7-Nonene Flower SPME-GC-MS Volatile components Ren et al. (2018) 194 Aaromatic alcohol Flower SPME-GC-MS Volatile components Ren et al. (2018) 195 Acetic acid Flower SPME-GC-MS Volatile components Ren et al. (2018) 196 Acetic acid hexyl ester Flower SPME-GC-MS Volatile components Ren et al. (2018) 197 Acetic acid, heptyl ester Flower SPME-GC-MS Volatile components Ren et al. (2018) 198 Acetophenone Flower SPME-GC-MS Volatile components Ren et al. (2018) (continued on next page) Y. Fan et al. (Li, 2009). The major bioactive components in A. truncatum leaves are flavonoids, which have been proven by many in vitro and in vivo experiments to have antitumor effects through the mechanisms like inhibiting signal transduction in cancer cells, reducing protein kinase activity, delaying or blocking the proliferation of cancer cells and inducing apoptosis of cancer cells (Gong et al., 2003;Kamsteeg et al., 2003;Li, 2009). Pentagalloyl glucoside (PGG) isolated from A. truncatum leaves is also considered as one of the major active ingredients (Zhao et al., 2011), which has effects on prostate cancer cell strains LNCaP and DU145, lung cancer cell strain LLC, liver cancer cell strain SK-HEP-1, breast cancer cell strain MCF-7, leukemia HL-60, small Murine melanoma cancer cell strain B16F10 and other cancer cells have significant cytotoxicity, which fully reveals the broad-spectrum antitumor activity of PGG Zhao et al., 2014). ...
Ethnopharmacological relevance
Acer truncatum Bunge is a multifunctional plant in northern China. It has traditionally been used to prevent cardiovascular and cerebrovascular diseases and treat skin trauma by different linguistic groups including Mongolian, Tibetan, and Korean. Although research has verified that A. truncatum contains a variety of active ingredients, especially nervonic acid, an important component in delaying brain aging, to date no review has been made to compile its traditional use, phytochemistry, and pharmacology.
Aims of the review
This review aimed to update the traditional uses, phytochemistry, and pharmacology of A. truncatum, which expect to provide theoretical support for the future utilization as well as highlight the further investigation of this important plant.
Materials and methods
The ethnobotanical, phytochemical, and pharmacological information related to A. truncatum from 1949 to March 2021 were collated by surveying the traditional medicinal books and ethnomedicinal publications and searching the online databases including Google Scholar, Sci Finder, Web of Science, Springer Link, PubMed, Wiley, China National Knowledge Infrastructure (CNKI), Baidu Scholar, and Wan Fang Database.
Results
A. truncatum has traditionally been used for medicinal, edible and ornamental purposes in northern China for many centuries. Different parts of the plant including leaves, fruits and bark, are mainly used as herbal medicine to treat hyperpiesia, hyperlipidemia, bruises, back pain, etc. A total of 288 compounds in A. truncatum, including polyphenols, organic acids or lipids, and biological volatile organic compounds were isolated or identified by phytochemical studies. Pharmacological research showed that A. truncatum has various bioactivities such as acetylcholinesterase inhibition, antibacterial, antioxidant, antitumor, and fatty acid synthase inhibition effects.
Conclusion
A. truncatum has been used as a traditional herbal medicine for centuries in northern China. Polyphenols, organic acids, lipids and other compounds were isolated or identified from different parts of the plant. Most of the pharmacological activities of A. truncatum have been reported, which showed its potential in the development of new drugs or nutraceuticals. However, detailed information on the molecular mechanisms, metabolic activity, and toxicology of active components is limited. Further comprehensive research to evaluate the medicinal properties of A. truncatum will be necessary.
... Genomic profiling has identified HER2 as a druggable molecular target, and its monoclonal antibodies, such as TZB and zanidatamab, have demonstrated excellent clinical efficacy in HER2-positive GBC [40][41][42] . In most HER2-positive tumors, elevated HER2 regulates PI3K-Akt signaling to activate the nuclear translocation of the NFκB-p65/p50 complex, resulting in the release of inflammatory cytokines and growth factors that inhibit apoptosis and promote tumor proliferation, angiogenesis, and tumor invasion 35,[43][44][45] . However, HER2 antibody resistance and cardiotoxicity pose clinical challenges. ...
Phototherapy of deep tumors still suffers from many obstacles, such as limited near-infrared (NIR) tissue penetration depth and low accumulation efficiency within the target sites. Herein, stimuli-sensitive tumor-targeted photodynamic nanoparticles (STPNs) with persistent luminescence for the treatment of deep tumors are reported. Purpurin 18 (Pu18), a porphyrin derivative, is utilized as a photosensitizer to produce persistent luminescence in STPNs, while lanthanide-doped upconversion nanoparticles (UCNPs) exhibit bioimaging properties and possess high photostability that can enhance photosensitizer efficacy. STPNs are initially stimulated by NIR irradiation before intravenous administration and accumulate at the tumor site to enter the cells through the HER2 receptor. Due to Pu18 afterglow luminescence properties, STPNs can continuously generate ROS to inhibit NFκB nuclear translocation, leading to tumor cell apoptosis. Moreover, STPNs can be used for diagnostic purposes through MRI and intraoperative NIR navigation. STPNs exceptional antitumor properties combined the advantages of UCNPs and persistent luminescence, representing a promising phototherapeutic strategy for deep tumors.
... Natural steroidal ligands such as dihydrotestosterone, estradiol, and cholesterol are the ones with whom genistein shows some of the geometric features like polar terminal hydroxyl group, and multiring hydrophobic core [24,25]. Genistein can specifically inhibit protein tyrosine kinases B (AKT) [26]; induce apoptosis of cancer cells [27]; regulate epidermal growth factor receptor and insulin-like growth factor I receptor; and regulate 5α reductase metastasis, DNA topoisomerase II, protein histidine kinase, angiogenesis [28], antiproliferative and proapoptotic activity by downregulating the activated nuclear factor kappa light-chain enhancer of activated B cells (NFкB) signaling pathway [29,30]. The mechanism of action of genistein is represented in Fig. 2. ...
Genistein is typical soy isoflavone, having cytotoxic potential toward different types of cancer cells. The success of the delivery of genistein for therapeutic application is restricted due to its physicochemical characteristics. Genistein is a strong acidic drug and their pKa is 7.03 with a molecular weight of 270.241 g/mol. Genistein is having a limited solubility in water about 0.9 μg/ml categorized as slightly soluble in aqueous media. On other hand, its lipophilicity is very high. Its octanol-water partition coefficient is about log P 3.04. A high intestinal and hepatobiliary metabolism of genistein further makes hindrance to achieve desired bioavailability post systemic administration. This problem is handled by a nanotechnological approach easily and gets successful in various aspects. These innovative approaches provide targeted delivery of drugs to various tissues and involve treating large numbers of cancer such as skin, lung, brain, cervical, colon, breast, and leukaemia. The present review provides detailed information about the prospects of nanoparticles, vesicle carriers, disperse liquid crystals, and capsuled systems developed by nanotechnological approach to combat the traditional delivery challenge of this anti-cancer drug in success for skin cancer. Rather than overcoming the delivery challenge, this novel delivery system also enhances the therapeutic response by various means.
Graphical Abstract
... Classes of polyphenols with their commonly used agents, studied effects, and corresponding important literature. [168,169] Flavan-3-ol Epigallocatechin gallate Offers anti-viral and anti-bacterial effects Inhibits tumor necrosis factor-α (TNF-α)-induced production of monocyte chemoattractant protein-1 (MCP-1) [170,171] Isoflavone Daidzein Blocks the transcriptional activation of pro-inflammatory genes and decreases the mRNA level of Cxcl2 in TNF-α-treated cells Increases AMPK phosphorylation followed by GLUT 4 translocation and glucose uptake [172,173] Genistein Induces apoptosis through activation of caspase-1 Offers anti-proliferative effects through downregulation of DNA methylation Suppresses Akt activity, promoting deactivation of NF-κB [174][175][176] C. elegans provides a solid model for studying the effects of polyphenols on the aging system. The administration of substances to the nematode's natural diet is a suitable way to observe the effects of the compound on the animal [177]. ...
The study of aging is an important topic in contemporary research. Considering the demographic changes and the resulting shifts towards an older population, it is of great interest to preserve youthful physiology in old age. For this endeavor, it is necessary to choose an appropriate model. One such model is the nematode Caenorhabditis elegans (C. elegans), which has a long tradition in aging research. In this review article, we explore the advantages of using the nematode model in aging research, focusing on bioenergetics and the study of secondary plant metabolites that have interesting implications during this process. In the first section, we review the situation of aging research today. Conventional theories and hypotheses about the ongoing aging process will be presented and briefly explained. The second section focuses on the nematode C. elegans and its utility in aging and nutrition research. Two useful genome editing methods for monitoring genetic interactions (RNAi and CRISPR/Cas9) are presented. Due to the mitochondria's influence on aging, we also introduce the possibility of observing bioenergetics and respiratory phenomena in C. elegans. We then report on mitochondrial conservation between vertebrates and invertebrates. Here, we explain why the nematode is a suitable model for the study of mitochondrial aging. In the fourth section , we focus on phytochemicals and their applications in contemporary nutritional science, with an emphasis on aging research. As an emerging field of science, we conclude this review in the fifth section with several studies focusing on mitochondrial research and the effects of phytochemicals such as polyphenols. In summary, the nematode C. elegans is a suitable model for aging research that incorporates the mitochondrial theory of aging. Its living conditions in the laboratory are optimal for feeding studies, thus enabling bioenergetics to be observed during the aging process.
... In all normal cells, cyclin D1 and E bind to cyclin-dependent kinases (Cdk4 and Cdk2) that phosphorylate retinoblastoma (Rb), releasing the group of genes that encode the transcription factor in eukaryotes (E2F). Metabolites such as quercetin, curcumin, resveratrol, flavopiridol, and genistein have been reported to inhibit CDKs [135][136][137]. Most of the plantderived colorants influence and induce cell cycle arrest via DNA damage, causing apoptosis. ...
Despite the great advancements made in cancer treatment, there are still many unsatisfied aspects, such as the wide palette of side effects and the drug resistance. There is an obvious increasing scientific attention towards nature and what it can offer the human race. Natural products can be used to treat many diseases, of which some plant products are currently used to treat cancer. Plants produce secondary metabolites for their signaling mechanisms and natural defense. A variety of plant-derived products have shown promising anticancer properties in vitro and in vivo. Rather than recreating the natural production environment, ongoing studies are currently setting various strategies to significantly manipulate the quantity of anticancer molecules in plants. This review focuses on the recently studied secondary metabolite agents that have shown promising anticancer activity, outlining their potential mechanisms of action and pathways.
... Moreover, genistein can influence metastasis and induce apoptosis by inhibiting Akt, as well as NF-κB cascades, in PC3 cell lines and MDA-MB-231 breast cancer cell lines, as well as inhibiting the IL-6/STAT3 pathway in MDA-MB-453 breast cancer cell lines, thus inhibiting cell proliferation [272,290,291]. Furthermore, genistein decreases phosphorylated-Akt in HT-29 colon cancer cells [292], in LNCaP prostate cancer cells [293], and in HeLa and CaSki cervical cancer cell lines [294], as well as in other cancer cell cultures [272]. ...
Cancer is the second leading cause of death after cardiovascular diseases. Conventional anticancer therapies are associated with lack of selectivity and serious side effects. Cancer hallmarks are biological capabilities acquired by cancer cells during neoplastic transformation. Targeting multiple cancer hallmarks is a promising strategy to treat cancer. The diversity in chemical structure and the relatively low toxicity make plant-derived natural products a promising source for the development of new and more effective anticancer therapies that have the capacity to target multiple hallmarks in cancer. In this review, we discussed the anticancer activities of ten natural products extracted from plants. The majority of these products inhibit cancer by targeting multiple cancer hallmarks, and many of these chemicals have reached clinical applications. Studies discussed in this review provide a solid ground for researchers and physicians to design more effective combination anticancer therapies using plant-derived natural products.
... In rat model of transient middle cerebral artery occlusion, dietary GE plays neuroprotective roles by lower oxidative stress (Ma et al. 2010). Moreover, GE ameliorates inflammation-induced damage within tissues by suppressing the NfκB pathway (Gong et al. 2003). Previous study from our group has shown that GE prevents cognitive decline in amnesic mice by suppressing neuroinflammation and promoting the expression of neuro-protective genes in the hippocampus . ...
Genistein (GE) or 4′,5,7-trihydroxyflavone, a plant derived isoflavone, is a biologically active compound having several beneficial properties. Studies showed that GE possesses anti-neoplastic, anti-tumor, anti-helminthic, anti-oxidant, and anti-inflammatory activities. Herein, we investigated the neuroprotective effects of GE in a mouse model of hypoxia-induced amnesia. Mice were exposed to hypoxic conditions (10% O2) in a designated hypoxia chamber and co-treated with GE (10, 20, or 30 mg/kg) for 4 weeks. Following this, behavioral tests were performed to evaluate memory performance. We assessed microglial activation in the hippocampus, amygdala, and pre-frontal cortex (PFC) regions by evaluating the Iba-1 and GFAP transcript levels, and MIP-1β, Cox-2, and IL6 protein levels. Apoptosis was assessed by evaluating Bax, BAD, and Bcl-2 mRNA levels, and caspase-3 activity. To uncover the underlying molecular mechanism, we evaluated the levels of Nrf2, HO-1, and NQO1 in different brain regions of mice from all groups. Results showed that hypoxia-exposed mice have reduced performance in the behavioral tests and GE treatment enhanced the memory performance in hypoxia-exposed mice. Moreover, hypoxia-exposed mice showed increased expression of microglial activation markers and enhanced apoptosis in the hippocampus, amygdala, and PFC. GE treatment suppressed microglial activation and prevented apoptosis in the brain of hypoxia-exposed mice. Furthermore, hypoxia-exposure reduced the expression of Nrf2, NQO1, and HO-1 while GE treatment ameliorated this decrease in different regions of hypoxia-exposed mice brain. In conclusion, GE prevents cognitive dysfunction by suppressing microglial activation and inhibiting apoptosis in the hypoxia-exposed mice brain.
... The inhibition of translocation of NF-jB resulted in decreased Akt phosphorylation. It has been known that there is a cross-talk between NF-jB and Akt signaling pathway [23]. Meng et al. demonstrated earlier that inhibition of NF-jB abrogated Akt phosphorylation (S473), supporting my Akt phosphorylation data [24]. ...
Methylglyoxal (MGO) is predominantly produced as a by-product of the glycolysis pathway. The glyoxalase system effectively removes it in a healthy organism. However, this process is impaired, and MGO level is elevated in people with diabetes. MGO's effects on proliferation were mostly studied in cancer cells, and the data in other cell types are limited. This study inspected the proliferative capacity of MGO in vascular smooth muscle cells (VSMCs), which have a crucial role in atherosclerosis and restenosis. The roles of ERK1/2 MAPK and Akt phosphorylations in proliferation were determined. Telmisartan, irbesartan, and NF-κB inhibitor JSH-23's roles in protecting the cells from MGO-induced proliferation were also investigated. Primary VSMCs were isolated from the rat aorta. The proliferation was spectrophotometrically measured by using a tetrazolium salt (Wst-1). The cells were cultured in standard media (SM, glucose conc. 5.5 mM) or high glucose media (HGM, glucose conc. 25 mM; an in vitro model of hyperglycemia). ERK1/2 MAPK and Akt phosphorylations were determined by the western blot method. MGO triggered the proliferation at 24, 48, and 72 hrs in SM and 48 and 72 hrs in HGM. Low doses of MGO such as 1-10 µM can induce proliferation. The phosphorylated ERK1/2 MAPK and Akt participated in MGO-induced proliferation. Telmisartan, irbesartan, and JSH-23 effectively alleviated the proliferation and Akt phosphorylation. MGO could proliferate VSMCs even at low doses. Moreover, hypertensive diabetic patients might benefit from a sartan family drug to protect VSMCs from MGO-induced proliferation.
... The biological mechanisms for soy isoflavones to reduce the risk of breast cancer may be related to preferential binding to ER-b relative to ER-a (30). Soy isoflavones may also act via estrogen-independent mechanisms, such as inhibiting the nuclear transcription factor jB DNA binding activity and the Akt signaling pathway (31), both of which are vital to maintaining a steady-state balance between survival and apoptosis of the cell. ...
Background
The diet-center hypothesis has gained much support from the apparent protective effect of the Mediterranean diet on breast cancer. However, the evidence of the association between Mediterranean diet adherence and breast cancer molecular subtypes remains small, especially in non-Mediterranean populations.
Methods
The subjects from the Chinese Wuxi Exposure and Breast Cancer Study, a population-based case-control study, included 818 patients and 935 healthy controls. A validated food frequency questionnaire used for diet assessment and a modified version of the alternate Mediterranean Diet Score, which is called the alternate Chinese Diet Score, was developed to assess adherence to a migrated Chinese version of the Mediterranean diet, which we called the vegetable-fruit-soy dietary pattern. Soy foods, rapeseed oil, and coarse cereals replaced legumes, olive oil, and whole grains reflecting the cuisine of the region. We examined the association between the vegetable-fruit-soy diet adherence and breast cancer risk, stratified by menopause status (pre- or postmenopausal) and receptor status [estrogen-receptor (ER), progesterone-receptor (PR) status, and human epidermal growth factor 2 (HER2)] oncogene expression, followed by five specific combinations (ER+, ER–, ER+/PR+,ER–/PR–, and ER–/PR–/HER2–).
Results
The results suggest that the vegetable-fruit-soy dietary pattern was inversely associated with postmenopausal breast cancer risk [4th vs. 1st quartile, odds ratio (OR) = 0.57, 95%CI = 0.41, 0.80; P trend < 0.001] and that the inverse association was somewhat stronger to detect among ER- subtypes (OR = 0.63; 95%CI = 0.37, 0.94; P trend = 0.003) and ER–/PR–subtypes (OR = 0.64; 95%CI = 0.41, 0.93; P trend = 0.012). We did not observe any significant association between the vegetable-fruit-soy diet characteristics and ER+ subtype, as well as between PR+ and ER+/PR+ subtypes.
Conclusion
The favorable influence from the Mediterranean diet may also apply to Chinese women. The vegetable-fruit-soy dietary pattern may reduce the risk of postmenopausal breast cancer, particularly among ER- subtype, and ER–/PR–subtype.
... Isoflavone reduces inflammation by targeting various signaling pathways mediated by NF-jB, AP-1, PPAR, Nrf2, and MAPKs (Chen et al. 2018b). For example, genistein possesses multiple biological activities, such as inhibiting tyrosine kinase (Akiyama et al. 1987), topoisomerase II (Okura et al. 1988), NF-jB (Gong et al. 2003), and cancer cell proliferation (Wang et al. 2012). Genistein also exerts vascular protective effects by acting on the signaling molecules in vascular endothelial cells and thus preventing heart-related disorders (Si and Liu 2008). ...
Isoflavonoids, a class of flavonoid polyphenolic compounds, are found primarily in leguminous plants. The chemical structure of isoflavonoid is a rearranged 2-phenyl of the flavonoids to a 3-phenyl by substituting the C-ring. Consuming dietary isoflavonoids provides many health benefits, including protection against age-related diseases, such as post-menopausal problems, osteoporosis, cardiovascular diseases, and hormone-dependent cancer. Since the market for isoflavonoids is growing, there is a need for alternative strategies for producing isoflavonoids from sustainable sources. In vitro suspension cell culture is environmentally friendly, and its conditions can be easily manipulated to enhance the yield of isoflavonoids. This review provides a detailed survey of the strategies used to augment the production of isoflavonoids with a particular emphasis on media optimization, elicitation, application of electric field, and metabolic engineering.
... Research results revealed that genistein pretreatment caused the inactivation of NF-κB activity, which increased cell growth inhibition and apoptosis with therapeutic doses of cisplatin, docetaxel, or gemcitabine [119]. Gong and coworkers reported the inactivation of NF-κB by genistein in MDA-MB-231 breast cancer cells partly mediated via the Akt pathway [120]. Furthermore, genistein inhibited the growth of MDA-MB-231 triple-negative breast cancer cells by inhibiting NF-κB activity via the Notch-1 signalling pathway in a dose-dependent manner, as reported by Pan H et al. [121]. ...
Nuclear factor-kappa B (NF-κB) is one of the principal inducible proteins that is a predominant transcription factor known to control the gene expression in mammals and plays a pivotal role in regulating cell signalling in the body under certain physiological and pathological conditions. In cancer cells, such as colon, breast, pancreatic, ovarian, melanoma, and lymphoma, the NF-κB pathway has been reported to be active. In cellular proliferation, promoting angiogenesis, invasion, metastasis of tumour cells and blocking apoptosis, the constitutive activity of NF-κB signalling has been reported. Therefore, immense attention has been given to developing drugs targeting NF-κB signalling pathways to treat many types of tumours. They are a desirable therapeutic target for drugs, and many studies concentrated on recognizing compounds. They may be able to reverse or standstill the growth and spread of tumours that selectively interfere with this pathway. Recently, numerous substances derived from plants have been evaluated as possible inhibitors of the NF-κB pathway. These include various compounds, such as flavonoids, lignans, diterpenes, sesquiterpenes, polyphenols, etc. A study supported by folk medicine demonstrated that plant-derived compounds could suppress NF-κB signalling. Taking this into account, the present review revealed the anticancer potential of naturally occurring compounds which have been verified both by inhibiting the NF-κB signalling and suppressing growth and spread of cancer and highlighting their mechanism of NF-κB inhibition.
... In addition, a study showed that soy supplement reduced IL-6 though decrease in abdominal fat, since IL-6 is produced by subcutaneous abdominal fat [45]. Also, soy isoflavones could downregulate IL-6 via its transcription factor nuclear factor K β (NF-K β ) [46]. The function of soy isoflavones through their anti-oxidant properties is well known in the prevention and treatment of various diseases. ...
... This cross-talk can modulate AMPK activity in the heart both under basal conditions in situ and during DXR perfusion [34]. The inhibitory effects of the soy-based diet on Akt and ERK could be mediated by genistein, known to inhibit Tyr kinases (for a review, see [54]) and to have an anti-proliferative effect, consistent with indirect AMPK activation [55][56][57][58][59]. The activation of Akt and ERK seen with Cr supplementation was also reported for skeletal muscle [60,61] and suggested by recent database meta-analysis [62]. ...
Nutritional habits can have a significant impact on cardiovascular health and disease. This may also apply to cardiotoxicity caused as a frequent side effect of chemotherapeutic drugs, such as doxorubicin (DXR). The aim of this work was to analyze if diet, in particular creatine (Cr) supplementation, can modulate cardiac biochemical (energy status, oxidative damage and antioxidant capacity, DNA integrity, cell signaling) and functional parameters at baseline and upon DXR treatment. Here, male Wistar rats were fed for 4 weeks with either standard rodent diet (NORMAL), soy-based diet (SOY), or Cr-supplemented soy-based diet (SOY + Cr). Hearts were either freeze-clamped in situ or following ex vivo Langendorff perfusion without or with 25 μM DXR and after recording cardiac function. The diets had distinct cardiac effects. Soy-based diet (SOY vs. NORMAL) did not alter cardiac performance but increased phosphorylation of acetyl-CoA carboxylase (ACC), indicating activation of rather pro-catabolic AMP-activated protein kinase (AMPK) signaling, consistent with increased ADP/ATP ratios and lower lipid peroxidation. Creatine addition to the soy-based diet (SOY + Cr vs. SOY) slightly increased left ventricular developed pressure (LVDP) and contractility dp/dt, as measured at baseline in perfused heart, and resulted in activation of the rather pro-anabolic protein kinases Akt and ERK. Challenging perfused heart with DXR, as analyzed across all nutritional regimens, deteriorated most cardiac functional parameters and also altered activation of the AMPK, ERK, and Akt signaling pathways. Despite partial reprogramming of cell signaling and metabolism in the rat heart, diet did not modify the functional response to supraclinical DXR concentrations in the used acute cardiotoxicity model. However, the long-term effect of these diets on cardiac sensitivity to chronic and clinically relevant DXR doses remains to be established.
... In addition, a study showed that soy supplement reduced IL-6 though decrease in abdominal fat, since IL-6 is produced by subcutaneous abdominal fat [45]. Also, soy isoflavones could downregulate IL-6 via its transcription factor nuclear factor K β (NF-K β ) [46]. The function of soy isoflavones through their anti-oxidant properties is well known in the prevention and treatment of various diseases. ...
Decreased adiponectin levels has been demonstrated in postmenopausal (PMP) women. Soy isoflavones, as an herbal product have been shown to increase adiponectin level but the results are inconclusive and inconsistent. The present study reassessed the data on the impact of soy isoflavones supplementation on adiponectin levels in PMP women through a meta-analysis. A systematic search was performed in the databases of PubMed, Web of science, Scopus and the Cochrane library. The literature search identified 830 studies with duplicates. Out of those, 80 were screened for title and abstract and 12 articles were ultimately selected for the analysis. Meta-regression and subgroup analyses, based on the moderator variables such as treatment duration, dose of soy isoflavones and BMI were performed. The quality of the studies was evaluated using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. The results revealed that soy isoflavones supplementation significantly increased the circulating level of adiponectin in PMP women (SMD: 0.36 µg/mL; 95% CI (0.05 to 0.66); P= 0.02). No publication bias was observed using Begg's (P = 0.38) and Egger's (P = 0.07) tests. Sensitivity analysis indicated the results were completely powerful and stable. Moreover, Meta-regression and subgroup analyses indicated a significant increase of adiponectin levels in subgroups of dose > 50 mg and treatment duration less or equal 3 months. Our findings showed significantly increase in adiponectin levels after isoflavones-supplemented soy consumption in postmenopausal women, who received dose > 50 mg of soy isoflavones in treatment duration ≤ 3 months.
... The genetic and genomic studies have revealed new paths that are activated in various breast cancers, in which somatic mutations occur due to the gain or loss of key genes within the phosphoinositide 3-kinase pathway (PI3K) [37]. PI3K pathway was reported to have alterations in many cases of breast cancers and leads to therapeutic resistance. ...
Cancer is one of the most common malignant diseases that occur worldwide, among which breast cancer is the second leading cause of death in women. The subtypes are associated with differences in the outcome and were selected for treatments according to the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor. Triple-negative breast cancer, one of the subtypes of breast cancer, is difficult to treat and can even lead to death. If breast cancer is not treated during the initial stages, it may spread to nearby organs, a process called metastasis, through the blood or lymph system. For in vitro studies, MCF-7, MDA-MB-231, MDA-MB-468, and T47B are the most commonly used breast cancer cell lines. Clinically, chemotherapy and radiotherapy are usually expensive and can also cause side effects. To overcome these issues, medicinal plants could be the best alternative for chemotherapeutic drugs with fewer side effects and cost-effectiveness. Furthermore, the genes involved in breast cancer can be regulated and synergized with signaling molecules to suppress the proliferation of breast cancer cells. In addition, nanoparticles encapsulating (nano-encapsulation) medicinal plant extracts showed a significant reduction in the apoptotic and cytotoxic activities of breast cancer cells. This present review mainly speculates an overview of the native medicinal plant-derived anti-cancerous compounds with its efficiency, types, and pathways involved in breast cancer along with its genes, the mechanism of breast cancer brain metastasis, chemoresistivity and its mechanism, bioinformatics approaches which could be an effective alternative for drug discovery.
... The mechanism of action of this isoflavone to inhibit cancer cell growth involves cell cycle arrest [111] and modulation of genes related to apoptosis. Specifically, genistein inhibits the activation of NFκβ and AKT signaling pathways [112,113], inhibits the topoisomerase I and II, 5α-reductase, and protein histidine kinase. In addition, genistein acts as an antioxidant and is considered a potent inhibitor of angiogenesis and metastasis [114]. ...
Preclinical, clinical, and epidemiological studies indicate that vitamin D3 (VD) deficiency is a risk factor for the development of breast cancer. Underlying mechanisms include the ability of calcitriol to induce cell differentiation, inhibit oncogenes expression, and modify different signaling pathways involved in the control of cell proliferation. In addition, calcitriol combined with different kinds of antineoplastic drugs has been demonstrated to enhance their beneficial effects in an additive or synergistic fashion. However, a recognized adjuvant regimen based on calcitriol for treating patients with breast cancer has not yet been fully established. Accordingly, in the present work, we review and discuss the preclinical and clinical studies about the combination of calcitriol with different oncological drugs, aiming to emphasize its main therapeutic benefits and opportunities for the treatment of this pathology.
... The deposition of collagen in mice lungs, evaluated after a 4-week interval, was also reduced [46,47]. Moreover, BIO 300 could suppress the expression and activation of NF-kB factor, responsible for an increase in inflammatory cytokines production, which occurs in the human cells infected by Sars-Cov-2 [48]. Considering the similarity between radiation-induced pneumonia and COVID-induced interstitial lung involvement [49], BIO300 is currently considered a candidate agent for treating COVID-19 patients discharged from the hospital who present residual functional impairment. ...
Introduction: Lung injury in severe COVID-19 pneumonia can rapidly evolve to established pulmonary fibrosis, with prognostic implications in the acute phase of the disease and long-lasting impact on the quality of life of COVID-19 survivors. This is an emerging medical need, and it has been hypothesized that antifibrotic treatments could have a role in ameliorating the fibrotic process in the lungs of these patients.
Areas covered: The safety and efficacy of available antifibrotic drugs (nintedanib and pirfenidone) and novel promising agents are being assessed in several ongoing clinical trials that were performed either in critically ill patients admitted to intensive care, or in discharged patients presenting fibrotic sequalae from COVID-19. Literature search was performed using Medline and Clinicaltrials.org databases (2001-2021).
Expert opinion: Despite the strong rationale support the use of antifibrotic therapies in COVID-related fibrosis, there are several uncertainties regarding the timing for their introduction and the real risks/benefits ratio of antifibrotic treatment in the acute and the chronic phases of the disease. The findings of ongoing clinical trials and the long-term observation of longitudinal cohorts will eventually clarify the best management approach for these patients.
... In addition, genistein can prevent the proliferation of primary rhabdomyosarcoma, glioblastoma, embryonic carcinoma, and hepatocellular carcinoma cells, arrest cell cycle progression, and induce apoptosis [113]. It was also shown to reduce the adhesion and metastasis of prostate, lung, breast, and pancreas cancer cells by suppressing NF-κB, and protein kinase B transcription factors [114][115][116]. The combination of genistein with sorafenib was shown to improve the sensitivity of sorafenib-resistant hepatocellular carcinoma cell lines [111]. ...
Background:
Tumorigenesis is associated with deregulation of nutritional requirements, intermediary metabolites production, and microenvironment interactions. Unlike their normal cell counterparts, tumor cells rely on aerobic glycolysis, through the Warburg effect.
Summary:
The pentose phosphate pathway (PPP) is a major glucose metabolic shunt that is upregulated in cancer cells. The PPP comprises an oxidative and a nonoxidative phase and is essential for nucleotide synthesis of rapidly dividing cells. The PPP also generates nicotinamide adenine dinucleotide phosphate, which is required for reductive metabolism and to counteract oxidative stress in tumor cells. This article reviews the regulation of the PPP and discusses inhibitors that target its main pathways. Key Message: Exploiting the metabolic vulnerability of the PPP offers potential novel therapeutic opportunities and improves patients' response to cancer therapy.
... Specifically, GE treatment induces apoptosis and cell-cycle arrest and targets various signaling pathways including Akt, HIF-1α and VEGF pathways. GE has shown synergistic effects when combining with other conventional anticancer drugs in breast cancer treatment [13,59,60]. Pintova et al. tested the safety of GE when co-administrated with Fluorouracil and Oxaliplatin (FOLFOX) with or without the anti-angiogenic agent, Bevacizumab, in colorectal cancer patients. ...
Consumption of dietary natural components such as genistein (GE) found in soy-rich sources is strongly associated with a lower risk of breast cancer. However, bioactive dietary component-based therapeutic strategies are largely understudied in breast cancer treatment. Our investigation sought to elucidate the potential mechanisms linking bioactive dietary GE to its breast cancer chemotherapeutic potential in a special subtype of aggressive breast cancer—triple-negative breast cancer (TNBC)—by utilizing two preclinical patient-derived xenograft (PDX) orthotopic mouse models: BCM-3204 and TM00091. Our study revealed that administration of GE resulted in a delay of tumor growth in both PDX models. With transcriptomics analyses in TNBC tumors isolated from BCM-3204 PDXs, we found that dietary soybean GE significantly influenced multiple tumor-regulated gene expressions. Further validation assessment of six candidate differentially expressed genes (DEGs)—Cd74, Lpl, Ifi44, Fzd9, Sat1 and Wwc1—demonstrated a similar trend at gene transcriptional and protein levels as observed in RNA-sequencing results. Mechanistically, GE treatment-induced Cd74 downregulation regulated the NF-κB/Bcl-xL/TAp63 signal pathway, which may contribute to soybean GE-mediated therapeutic effects on TNBC tumors. Additionally, our findings revealed that GE can modify expression levels of key epigenetic-associated genes such as DNA methyltransferases (Dnmt3b), ten-eleven translocation (Tet3) methylcytosine dioxygenases and histone deacetyltransferase (Hdac2), and their enzymatic activities as well as genomic DNA methylation and histone methylation (H3K9) levels. Collectively, our investigation shows high significance for potential development of a novel therapeutic approach by using bioactive soybean GE for TNBC patients who have few treatment options.
... In MDA-MB-231, BC cell growth controlling is a significant target for Genistein. Gong et al. state that Gen (5-50 µM) inhibits cell growth by partly inducing apoptosis via downregulation of the Akt, NF-κB cascade pathways in vitro study [70]. Another in vitro analysis displayed the cell growth inhibitory activity was evident by Genistein (2.5-400µm) through the up-regulation of two crucial TSGs e,g. ...
Breast cancer (BC) is the most common type of cancer in both men and women alike, but it is more prevalent in women. Natural compounds that can modulate the oncogenic process can be considered a significant anti-cancer agent for treating BC. These natural compounds are more effective than synthetic drugs, which have profound side effects on the normal cell and resistance to cancer cells. Genistein is a type of dietary phytoestrogen included in the flavonoid group with a similar structure of estrogen that might provide a strong alternative and complementary medicine to existing chemotherapeutics drugs. Several research studies demonstrated that it can target the estrogen receptor (ER), Human epidermal growth factor receptor-2 (HER2), and Breast cancer gene-1 (BRCA-1) in multiple BC cell lines, as well as sensitize cancer cell lines to this compound when used at an optimal inhibitory concentration. Genistein effectively showed anti-cancer activities through apoptosis induction, arresting cell cycle, inhibiting angiogenesis with metastasis, reducing inflammation, mammosphere formation, tumor growth, up-regulating tumor suppressor gene, and downregulating oncogene in suppressing cancer progression in vitro and animal model study. In addition, research studies have also suggested that these phytochemicals synergistically reverse the resistance mechanism of chemotherapeutic drugs, increasing the efficacy of some chemoinformatics drugs. Our review article aims to unbox and validate the molecular pharmacology in breast tissue, cell-specific anti-cancer mechanism with synergistic activity, and possible pharmacokinetic parameters of Genistein as a potential alternative therapeutic option for the treatment of BC.
... As genistein could inactivate NF-kB [78], which has been shown to reduce inflammation in a COVID mouse model, it could be effective in treating lung complications caused by the SARS-CoV-2 infection. ...
At the end of 2019, a highly contagious infection began its ominous conquest of the world. It was soon discovered that the disease was caused by a novel coronavirus designated as SARS-CoV-2, and the disease was thus abbreviated to COVID-19 (COVID). The global medical community has directed its efforts not only to find effective therapies against the deadly pathogen but also to combat the concomitant complications. Two of the most common respiratory manifestations of COVID are a significant reduction in the diffusing capacity of the lungs (DLCO) and the associated pulmonary interstitial damage. One year after moderate COVID, the incidence rate of impaired DLCO and persistent lung damage still exceeds 30%, and one-third of the patients have severe DLCO impairment and fibrotic lung damage. The persistent respiratory complications may cause substantial population morbidity, long-term disability, and even death due to the lung fibrosis progression. The incidence of COVID-induced pulmonary fibrosis caused by COVID can be estimated based on a 15-year observational study of lung pathology after SARS. Most SARS patients with fibrotic lung damage recovered within the first year and then remained healthy; however, in 20% of the cases, significant fibrosis progression was found in 5–10 years. Based on these data, the incidence rate of post-COVID lung fibrosis can be estimated at 2–6% after moderate illness. What is worse, there are reasons to believe that fibrosis may become one of the major long-term complications of COVID, even in asymptomatic individuals. Currently, despite the best efforts of the global medical community, there are no treatments for COVID-induced pulmonary fibrosis. In this review, we analyze the latest data from ongoing clinical trials aimed at treating post-COVID lung fibrosis and analyze the rationale for the current drug candidates. We discuss the use of antifibrotic therapy for idiopathic pulmonary fibrosis, the IN01 vaccine, glucocorticosteroids as well as the stromal vascular fraction for the treatment and rehabilitation of patients with COVID-associated pulmonary damage.
... It has been shown that there is homology between the effects of DMBA on rats and estrogens, which can contribute to accelerating tumour development (30). It is also worth mentioning that one study described the occurrence of estrogen receptors after induction of breast tumours using DMBA (31). Considering the histopathological results and the concentration of methyl derivatives, it seems that nanogenistein stimulates cancer cells the most and tumours appear relatively quickly. ...
Background/aim:
The aim of the study was to assess the impact of nano-, micro-, and macro-sized-genistein on the growth and development of neoplasms in rats with mammary cancer. Additionally, the effect on the kinetics of changes (9-11-17-20 week of a rat's life) in the levels of methyl derivatives: 1-methyladenine, 3-methyladenine, 7-methylguanine, 1-methylguanine, 1-methyladenosine, 7-methylguanosine, O-methyl-guanosine and N6-methyl-2'-deoxyguanosine in the urine of rats was analyzed.
Materials and methods:
Female Sprague-Dawley rats divided into 4 groups were used in the study. Animals were fed only a control diet or diets supplemented with the nano-, micro- and macro-sized genistein. To induce the mammary adenocarcinoma, rats were treated with 7,12-dimethylbenz[a]anthracene (DMBA). Modified nucleosides were determined by a high-performance liquid chromatography coupled to mass spectrometry method (LC-MS/MS).
Results:
The supplementation of the diet of animals with genistein resulted in an increase in the excretion of methylated derivatives in the urine of rats. In the animals receiving standard diet, the levels of methyl derivatives increased during the study or remained relatively low. In the case of animals whose diet was supplemented with the various forms of genistein, the levels of methylated derivatives were very high from the beginning.
Conclusion:
High levels of methyl derivatives can influence carcinogenesis.
... In addition, the development of characteristics of drug resistance in cancer cells, the development of new therapeutic agents against cancer is a crying need in recent times. Several studies have shown that plant extracts or phytochemicals are purified and have executed significant positive results in cancer treatment by using directly or in combination with existing drugs [21]. Various well-known phytochemicals are found to exhibit a specific action against tumors, breast cancer, and prostate cancer [22]. ...
Background: Colorectal cancer is considered the third most fetal among all type of cancer. Spleen tyrosine kinase (SYK) is a non-receptor type tyrosine-protein that plays crucial role in sig-naling mediated via immune receptor. We adopted an onco-informatics analysis to evaluate the SYK expression and prognostic value of SYK in colorectal cancer, and identification of potential phyto-chemicals which may inhibit overexpression of SYK protein as well as minimized colorectal cancer. Materials & Methods: Differential expression of SYK gene was analyzed using the several tran-scriptomic databases including Oncomine, UALCAN, GENT2 and GEPIA2. The server, cBioPortal was used to analyze mutation and copy number alterations whereas GENT2, GEPIA, OncoLnc and PrognoScan were employed to examine the survival rate. A protein-protein interaction network of SYK and co-expressed genes of SYK was conducted via GeneMANIA. Considering SYK gene encoding protein as drug target, selected phytochemicals were assessed by molecular docking using PyRx 0.8 packages. YASARA molecular dynamics simulators were applied for the post validation of the molecular docking data. Results: We have observed significant overexpression of mRNA expression levels of SYK gene colorectal adenocarcinoma (COAD) samples compared with normal tissues. Significant methylation level and various genetic alterations are assembled in SYK gene which can lead to the development of colorectal cancer. As a result, lower level of SYK expression was related to the more chances of patients' survival by which all the outcomes from the multiple bioinformatics platforms and web resources have demonstrated the significant evidences that the SYK kinsase can possess as a potential biomarker for the treatment of colorectal cancer. Here, aromatic phytochemicals namely, Kaempferol and Glabridin targeting SYK showed more stability compared to controls and may be useful for the treatment of colorectal cancer. Conclusion: Our Preprints (www.preprints.org) | NOT PEER-REVIEWED | study showed dysregulated expression of SYK in colorectal cancer and potentiality to act as a bi-omarker for the prognosis of CRC. Moreover, we have shown phytochemicals (Kaempferol and Glabridin) target SYK as potential treatment strategies and drug repositioning potentiality in colo-rectal cancer.
... Genistein has been shown to reduce MDA-MB-231 cell proliferation at an IC 50 dose of 20 µM, inhibiting the NF-κB factor and regulating a G2/M phase arrest [28]. Furthermore, Gong et al performed different assays which led them to obtain a higher IC 50 dose of 50 µM, observing apoptosis induction by suppression of the NF-κB an PI3K/Akt pathways [29]. As a future perspective for this study, it will be vital to analyse the diverse cell signalling pathways that contribute to the execution of the therapeutic effect of isoflavones on breast cancer, thus providing a clearer perspective on the mechanism of action exerted by isoflavones. ...
Background
Cancer is a homogenous group of diseases characterized by the dysregulation of normal cell physiological processes, such as proliferation, growth, and migration. In Mexico, cancer accounts for one of the main causes of death. Among the most common types of cancer which affect the Mexican population are breast, cervical, and colon cancers.
Objective
In the current research, we studied the effects of phenolic compounds of soy (Glycine max), isoflavones – available as a nutraceutical commercial product – on the proliferation of several cancer cell lines.
Methods
Firstly, we carried out a series of experiments of simulated chemical digestion to later determine the integrity and functionality of active compounds contained in capsule commercial products after their chemical digestion. Later on, we performed thin-layer chromatography, Ultraviolet/Visible spectrophotometry, and an analysis of the antioxidant activity of the phenolic compounds, and we assessed the effects on the proliferation of several cancer cell lines.
Results
By using such techniques, we demonstrated that soy isoflavones maintained their integrity and activity, even after being chemically digested. Moreover, our results showed there were several cases in which soy isoflavones did exert a noticeable effect over cell proliferation. Though the IC50 doses were different for each cell line, cell proliferation was, in fact, lower in all of them.
Conclusion
Our research provides strong evidence of the compelling antiproliferative effect of soy isoflavones in commercial product, even after simulated digestion, in distinct types of cancer. Hence, this represents a breakthrough to continue investigating phenolic compounds as potential coadjutants for anti-neoplastic treatments.
... Likewise, as mentioned above, resveratrol is linked with ER and SIRT1 activation and can synergistically promote and protect the proteostasis network. Similarly, genistein has been reported to activate ER, inhibit HSP90, and downregulate NF-kB and P13 K/Akt/HIF-1α signaling (Gong et al., 2003;Li and Sarkar, 2002;Tuli et al., 2019). Furthermore, recent reports have shown genistein accelerates mutant huntingtin degradation by correcting autophagy in cellular models of HD and fibroblasts derived from HD patients (Pierzynowska et al., 2018b(Pierzynowska et al., , 2019. ...
Defective proteostasis is associated with the gradual accumulations of misfolded proteins and is a hallmark of many age-associated neurodegenerative diseases. In the aged brain, maintenance of the proteostasis network presents a substantial challenge, and its loss contributes to the onset and progression of neurological diseases associated with cognitive decline due to the generation of toxic protein aggregates, a process termed 'proteinopathy'. Emerging evidence suggests that reversing proteinopathies by boosting proteostasis might provide an effective means of preventing neurodegeneration. From this perspective, phytochemicals may play significant roles as potent modulators of the proteostasis network, as previous reports have suggested they can interact with various network components to modify pathologies and confer neuroprotection. This review focuses on some potent phytochemicals that directly or indirectly modulate the proteostasis network and on their possible molecular targets. In addition, we propose strategies for the natural product-based modulation of proteostasis machinery that target proteinopathies.
... Although genistein has antiviral activity (229)(230)(231), it may also be useful to prevent radiationinduced lung damage. Genistein is thought to act through inactivation of NF-jB (232), and since NF-jB inhibition has been shown to reduce inflammation in a mouse model of COVID-19, it could be effective in treating lung complications caused by SARS-CoV-2 infection. Humanetics has announced initiation of a clinical trial in discharged COVID-19 patients, to determine if treatment with the oral BIO 300 product can reduce late lung fibrosis and improve quality of life in patients who are recovering from the infection (NCT04482595). ...
As the multi-systemic components of COVID-19 emerge, parallel etiologies can be drawn between SARS-CoV-2 infection and radiation injuries. While some SARS-CoV-2-infected individuals present as asymptomatic, others exhibit mild symptoms that may include fever, cough, chills, and unusual symptoms like loss of taste and smell and reddening in the extremities (e.g., ''COVID toes,'' suggestive of microvessel damage). Still others alarm healthcare providers with extreme and rapid onset of high-risk indicators of mortality that include acute respiratory distress syndrome (ARDS), multi-organ hypercoagulation, hypoxia and cardiovascular damage. Researchers are quickly refocusing their science to address this enigmatic virus that seems to unveil itself in new ways without discrimination. As investigators begin to identify early markers of disease, identification of common threads with other pathologies may provide some clues. Interestingly, years of research in the field of radiation biology documents the complex multiorgan nature of another disease state that occurs after exposure to high doses of radiation: the acute radiation syndrome (ARS). Inflammation is a key common player in COVID-19 and ARS, and drives the multi-system damage that dramatically alters biological homeostasis. Both conditions initiate a cytokine storm, with similar pro-inflammatory molecules increased and other anti-inflammatory molecules decreased. These changes manifest in a variety of ways, with a demonstrably higher health impact in patients having underlying medical conditions. The potentially dramatic human impact of ARS has guided the science that has identified many biomarkers of radiation exposure, established medical management strategies for ARS, and led to the development of medical countermeasures for use in the event of a radiation public health emergency. These efforts can now be leveraged to help elucidate mechanisms of action of COVID-19 injuries. Furthermore, this intersection between COVID-19 and ARS may point to approaches that could accelerate the discovery of treatments for both. © 2021 by Radiation Research Society. All rights of reproduction in any form reserved.
... 164 It also inactivates NF-kB via the Akt pathway. 165 Gn inhibits expression of Notch 1 166 and Wnt. 167 Curcumin has biological activity against inflammation, ischemia, and cancer (Fig. 8). ...
The tumor microenvironment (TME) is heterogeneous and contains a multiple cell population with surrounded immune cells, which plays a major role in regulating metastasis. The multifunctional pathways, Hedgehog (Hh), Wnt, Notch, and NF-kB, cross-regulates metastasis in breast cancer. This review presents substantial evidence for cross-regulation of TME components and signaling pathways, which makes breast TME more heterogeneous and complex, promoting breast cancer progression and metastasis as a highly aggressive form. We discoursed the importance of stromal and immune cells as well as their crosstalk in bridging the metastasis. We also discussed the role of Hh and Notch pathways in the intervention between breast cancer cells and macrophages to support TME; Notch signaling in the bidirectional communication between cancer cells and components of TME; Wnt signal pathway in controlling the factors responsible for EMT and NF-κB pathway in the regulation of genes controlling the inflammatory response. We also present the role of exosomes and their miRNAs in the cross-regulation of TME cells as well as pathways in the reprogramming of breast TME to support metastasis. Finally, we examined and discussed the targeted small molecule inhibitors and natural compounds targeting developmental pathways and proposed small molecule natural compounds as potential therapeutics of TME based on the multitargeting ability. In conclusion, the understanding of the molecular basis of the cross-regulation of TME pathways and their inhibitors helps identify molecular targets for rational drug discovery to treat breast cancers.
Breast cancer (BC) is the most diagnosed cancer worldwide, mainly affecting the epithelial cells from the mammary glands. When it expresses the estrogen receptor (ER), the tumor is called luminal BC, which is eligible for endocrine therapy with hormone signaling blockade. Hormone therapy is essential for the survival of patients, but therapeutic resistance has been shown to be worrying, significantly compromising the prognosis. In this context, the need to explore new compounds emerges, especially compounds of plant origin, since they are biologically active and particularly promising. Natural products are being continuously screened for treating cancer due to their chemical diversity, reduced toxicity, lower side effects, and low price. This review summarizes natural compounds for the treatment of luminal BC, emphasizing the activities of these compounds in ER-positive cells. Moreover, their potential as an alternative to endocrine resistance is explored, opening new opportunities for the design of optimized therapies.
TRPV6, a representative of the vanilloid subfamily of TRP channels, serves as the principal calcium uptake channel in the gut. Dysregulation of TRPV6 results in disturbed calcium homeostasis leading to a variety of human diseases, including many forms of cancer. Inhibitors of this oncochannel are therefore particularly needed. In this review, we provide an overview of recent advances in structural pharmacology that uncovered the molecular mechanisms of TRPV6 inhibition by a variety of small molecules, including synthetic and natural, plant-derived compounds as well as some prospective and clinically approved drugs.
Cancer cell plasticity plays a crucial role in tumor initiation, progression, and metastasis and is implicated in the multiple cancer defense mechanisms associated with therapy resistance and therapy evasion. Cancer resistance represents one of the significant obstacles in the clinical management of cancer. Some reversal chemosensitizing agents have been developed to resolve this serious clinical problem, but they have not yet been proven applicable in oncological practice. Activated nuclear factor kappa B (NF-κB) is a frequently observed biomarker in chemoresistant breast cancer (BC). Therefore, it denotes an attractive cellular target to mitigate cancer resistance. We summarize that flavonoids represent an essential class of phytochemicals that act as significant regulators of NF-κB signaling and negatively affect the fundamental cellular processes contributing to acquired cell plasticity and drug resistance. In this regard, flavokawain A, icariin, alpinetin, genistein, wogonin, apigenin, oroxylin A, xanthohumol, EGCG, hesperidin, naringenin, orientin, luteolin, delphinidin, fisetin, norwogonin, curcumin, cardamonin, methyl gallate and catechin-3-O-gallate, ampelopsin, puerarin, hyperoside, baicalein, paratocarpin E, and kaempferol and also synthetic flavonoids such as LFG-500 and 5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone have been reported to specifically interfere with the NF-κB pathway with complex signaling consequences in BC cells and could be potentially crucial in re-sensitizing unresponsive BC cases. The targeting NF-κB by above-mentioned flavonoids includes the modification of tumor microenvironment and epithelial-mesenchymal transition, growth factor receptor regulations, and modulations of specific pathways such as PI3K/AKT, MAP kinase/ERK, and Janus kinase/signal transduction in BC cells. Besides that, NF-κB signaling in BC cells modulated by flavonoids has also involved the regulation of ATP-binding cassette transporters, apoptosis, autophagy, cell cycle, and changes in the activity of cancer stem cells, oncogenes, or controlling of gene repair. The evaluation of conventional therapies in combination with plasticity-regulating/sensitizing agents offers new opportunities to make significant progress towards a complete cure for cancer.
Graphical abstract
Background:
Although cancers emerge rapidly and cancer cells divide aggressively, which affects our vital organ systems. Recently, cancer treatments are targeted immune systems mediating intrinsic cellular mechanisms. Natural efficacious polyphenols have been exhibited to help prevent most cancers and reverse the progression of cancers.
Methods:
Many resources have been used to know the promising role of polyphenols in preventing and treating cancers. The electronic databases include Science Direct, Google, Google Scholar, PubMed, and Scopus. The search was limited to the English language only.
Results:
Polyphenols have been reported as anti-metastatic agents that explore the promising role of these compounds in cancer prevention. Such agents act through many signaling pathways, including PI3K/Akt and TNF-induced signaling pathways. The chemical modifications of polyphenols and the structure-activity relationships (SARs) between polyphenols and anti-cancer activities have also been discussed.
Conclusion:
Many research papers were reported to explain the anti-cancer potential of Polyphenols, The SARs between polyphenols and anti-cancer activities, which correlate structures of polyphenols with significant chemotherapeutic action. The mechanism of anti-cancer potential is to be added for searching for new anti-cancer natural products.
Genistein, a commonly occurring isoflavone, has recently gained popularity owing to its ever-expanding spectrum of pharmacological benefits. In addition to health benefits such as improved bone health and reduced postmenopausal complications owing to its phytoestrogen properties, it has been widely evaluated for its anti-cancer potential. Several studies have established the potential for its usage in the management of breast, lung, and prostate cancers, and its usage has significantly evolved from early applications in traditional systems of medicine. This review offers an insight into its current status of usage, the chemistry, and pharmacokinetics of the molecule, an exploration of its apoptotic mechanisms in cancer management, and opportunities for synergism to improve therapeutic outcomes. In addition to this, the authors have presented an overview of recent clinical trials, to offer an understanding of contemporary studies and explore prospects for a greater number of focused trials, moving forward. Advancements in the application of nanotechnology as a strategy to improve safety and efficacy have also been highlighted, with a brief discussion of results from safety and toxicology studies.
Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. While significant effort has been invested in the development of synthetic TRPV6 inhibitors, natural channel blockers have been largely neglected. Here we report the structure of human TRPV6 in complex with the plant-derived phytoestrogen genistein, extracted from Styphnolobium japonicum, that was shown to inhibit cell invasion and metastasis in cancer clinical trials. Despite the pharmacological value, the molecular mechanism of TRPV6 inhibition by genistein has remained enigmatic. We use cryo-EM combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to show that genistein binds in the intracellular half of the TRPV6 pore and acts as an ion channel blocker and gating modifier. Genistein binding to the open channel causes pore closure and a two-fold symmetrical conformational rearrangement in the S4–S5 and S6-TRP helix regions. The unprecedented mechanism of TRPV6 inhibition by genistein uncovers new possibilities in structure-based drug design.
Women’s reproductive cancers are a group of cancers that initiate in women’s reproductive system including the cervix, ovaries, uterus, vagina and vulva. There are different risk factors and etiological mechanisms that are involved in oncogenesis of gynecologic malignancies. Exploration of effective chemopreventive and therapeutic approaches that are universally applied in most gynecologic cancers will be critically important and benefit women’s welfare. In the last two decades, novel strategies that target epigenetics-related molecular events have emerged as one of the major cancer prevention and therapies employed by dietary phytochemicals. These bioactive dietary components found in fruits and vegetables such as green tea, soybean, cruciferous vegetables, grapes and certain Asian spices have shown potent inhibitory activities against human cancer including female reproductive cancers. More important, these bioactive dietary compounds can elicit their chemopreventive/therapeutic properties through, at least in part, modulation of epigenetic processes including histone modification, DNA methylation and non-coding RNA expression during carcinogenesis. Given the fact that epigenetic aberrations dynamically contribute to cancer pathogenesis, reversal of abnormal epigenetic codes and their-induced gene expression profiles by bioactive dietary compounds could be an effective approach for gynecologic cancer prevention and therapy. In this review, we will discuss the advances in understanding the epigenetic effects of dietary phytochemicals on gene expression during cancer development, and how these epigenetics diets help to improve cancer prevention and treatment efficacy in major gynecologic cancers.
Cancer is the transformation of healthy cells into tumor cells in a multistage process that can affect any organ of the body. This disease is the second leading cause of death globally. There are now more than 10 million cancer cases per year worldwide, and the most common occurs in the lung, breast, and colon. Several studies demonstrate that lifestyle and eating habits are directly related to tumor cells’ appearance, such as high body mass index, low fruit and vegetable intake, lack of physical activity, and tobacco and alcohol use. It is widely believed that diet and nutrients can act as cancer risk-modifiers throughout the process of carcinogenesis, including initiation, promotion, progression, and/or conversion. Different plants have been the source of therapeutic agents. Plant-derived compounds have become indispensable for modern pharmacotherapy, and phenolic compounds are one of the most investigated due to their antitumor activity. Their cellular targets and mechanisms are compiled in the present work. Phenolic compounds are secondary metabolites present in large quantities in medicinal herbs and dietary plants (e.g., fruits, vegetables, and spices). They possess a diverse range of beneficial biological activities, which contribute to their potent effects on inhibiting carcinogenesis. Some benefits include cell proliferation and angiogenesis inhibition and anti-inflammatory, antioxidant, and antimetastatic activities. Thus, the present review supports the recommendations for consuming foods and drinks rich in phenolic compounds to prevent and possibly treat cancer.
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks receptors for targeted therapy. Consequently, chemotherapy is currently the mainstay of systemic treatment options. However, the enrichment of cancer stem cells (CSC, a subpopulation with stem-cell characteristics and tumor-initiating propensity) promotes chemo-resistance and tumorigenesis, resulting in cancer recurrence and relapse. Furthermore, toxic side effects of chemotherapeutics reduce patient wellbeing. Natural products, specifically compounds derived from plants, have the potential to treat TNBC and target CSCs by inhibiting CSC signaling pathways. Literature evidence from six promising compounds were reviewed, including sulforaphane, curcumin, genistein, resveratrol, lycopene, and epigallocatechin-3-gallate. These compounds have been shown to promote cell cycle arrest and apoptosis in TNBC cells. They also could inhibit the epithelial-mesenchymal transition (EMT) that plays an important role in metastasis. In addition, those natural compounds have been found to inhibit pathways important for CSCs, such as NF-κB, PI3K/Akt/mTOR, Notch 1, Wnt/β-catenin, and YAP. Clinicals trials conducted on these compounds have shown varying degrees of effectiveness. Epidemiological case-control studies for the compounds commonly consumed in certain human populations have also been summarized. While in vivo and in vitro data are promising, further basic and clinical investigations are required. Likely, natural products in combination with other drugs may hold great potential to improve TNBC treatment efficacy and patient outcomes.
Nrf2 (nuclear factor erythroid 2-related factor 2) and NF-κB (nuclear factor–kappa B) signaling pathways play a central role in suppressing or inducing inflammation and angiogenesis processes. Therefore, they are involved in many steps of carcinogenesis through cooperation with multiple signaling molecules and pathways. Targeting both transcription factors simultaneously may be considered an equally important strategy for cancer chemoprevention and therapy. Several hundreds of phytochemicals, mainly edible plant and vegetable components, were shown to activate Nrf2 and mediate antioxidant response. A similar number of phytochemicals was revealed to affect NF-κB. While activation of Nrf2 and inhibition of NF-κB may protect normal cells against cancer initiation and promotion, enhanced expression and activation in cancer cells may lead to resistance to conventional chemo- or radiotherapy. Most phytochemicals, through different mechanisms, activate Nrf2, but others, such as luteolin, can act as inhibitors of both Nrf2 and NF-κB. Despite many experimental data confirming the above mechanisms currently, limited evidence exists demonstrating such activity in humans. Combinations of phytochemicals resembling that in a natural food matrix but allowing higher concentrations may improve their modulating effect on Nrf2 and NF-κB and ultimately cancer prevention and therapy. This review presents the current knowledge on the effect of selected phytochemicals and their combinations on Nrf2 and NF-κB activities in the above context.
Epidemiological evidence indicates that a diet rich in fruits and vegetables lowers the risk of certain cancers. The cancer-lowering effect of fruits and vegetables is attributed, in part, to several compounds such as nondigestible polysaccharides, polyphenols present in these foods. Plant polyphenols are an integral part of the human and animal diet. The anticarcinogenic polyphenols act in various roles such as antioxidant, antiinflammatory, and the modulation of multiple pathways involved in tumor progression. Polyphenol classes such as flavonoids, phenolic acids, lignans, and stilbenes have anticarcinogenic properties. The polyphenols kill cancer cells and prevent metastasis by modulating DNA damage, cell cycle arrest, disruption of mitochondrial membrane, and nitric oxide production. This chapter describes the anticarcinogenic effects of polyphenols on cancer prevention and treatment.
Cancer, being the leading cause of death in the globe, has been one of the major thrust areas of research worldwide. In a new paradigm about neoplastic transformations, the initiation and recurrence of disease is attributed to few mutated cells in bulk of tumor called cancer stem cells (CSCs). CSCs have capacity of self-renewal and differentiation, which are known for resistance to radio and chemotherapy leading to recurrence of the disease even after treatment. Most of traditional drugs implicated in cancer therapy targeting primary tumors have substantial toxicity to the physiological system and have not been efficient in targeting these CSCs leading to poor prognosis. Targeting these CSCs in bulk of tumor might be novel strategy for cancer chemoprevention and therapeutics. Diet-derived interventions and diverse natural products are known to target these CSCs and related signaling pathways, namely, Wnt, Notch, and Hedgehog pathways, which are implicated for CSC self-renewal.
Practical applications
Cancer remains a global challenge even in this century. Poor prognosis, survival rate, and recurrence of the disease have been the major concerns in traditional cancer therapy regimes. Targeting cancer stem cells might be novel strategy for elimination and cure of the chronic disease as they are known to modulate all stages of carcinogenesis and responsible for recurrence and resistance to chemotherapy and radiotherapy. The evidence support that natural products might inhibit, delay, or reverse the process of tumorigenesis and modulate the different signaling pathways implicated for cancer stem cells self-renewal and differentiation. Natural products have minimal toxicity compared to traditional cancer therapy drugs since they have long been utilized in our food habits without any major side effects reported. Thus, targeting cancer stem cells with natural product might be a novel strategy for drug development in cancer chemoprevention and therapeutics.
The Wnt genes encode a large family of secreted polypeptides that mediate cell-cell communication in diverse developmental processes. The loss or inappropriate activation of Wnt expression has been shown to alter cell fate, morphogenesis and mitogenesis. Recent progress has identified Wnt receptors and components of an intracellular signalling pathway that mediate Wnt-dependent transcription. This review will highlight this 'core' Wnt signal-transduction pathway, but also aims to reveal the potential diversity of Wnt signalling targets. Particular attention will be paid to the overlap between developmental biology and oncogenesis, since recent progress shows Wnt signalling forms a paradigm for an interdisciplinary approach.
Breast-cancer incidence and mortality rates in different countries were found to be correlated with height, weight and age at menarche, all of which have been identified as risk factors in cohort or case-control studies of breast cancer. There were, however, correlations with total fat and animal protein consumption per capita even after controlling for the 3 anthropometric variables. This suggests that, while some of the effects of diet on breast-cancer rates may be mediated through effects on these known risk factors, there may be more direct effects as well.
Genistein, an in vitro inhibitor of topoisomerase II and tyrosine kinases, suppressed growth and induced differentiation in HL-205 cells, a clonal population of the human promyelocytic HL-60 leukemia cells, and in K-562-J cells, a clonal population of the human erythroid K-562 leukemia cells. Maturing HL-205 cells acquired either granulocytic or monocytic markers, namely, reactivity with the murine OKM1 monoclonal antibody, expression of nitroblue tetrazolium dye reduction, and staining for nonspecific esterase. The maturing K-562-J cells stained with benzidine, which indicates the presence of hemoglobin, an erythroid maturation marker. Although the acquisition of the maturation markers in both HL-205 and K-562-J cells was time dependent up to 6 days, the kinetics of this induction differed between the two cell types. Despite the in vitro inhibitory effect of genistein, treatment of either HL-205 or K-562-J cells with 150 micrograms/ml genistein for up to 16 h did not alter topoisomerase II activity (as determined by the unknotting assay) in their nuclear extracts. Analysis with the anti-phosphotyrosine PY-20 murine monoclonal antibody indicated that treatment of K-562-J cells with genistein decreased the reactivity of the antibody with two of the cellular proteins. However, no reactivity with the PY-20 antibody was detected in untreated or genistein-treated HL-205 cells. An early event in the HL-205 and K-562-J cells, occurring after only 1 h of treatment with 30-200 micrograms/ml genistein, was the induction of DNA damage as measured by an alkaline elution assay. This damage may be a contributing factor in the genistein-induced cell differentiation in the HL-205 and K-562-J cells.
Tyrosine-specific protein kinase activity of the epidermal growth factor (EGF) receptor, pp60v-src and pp110gag-fes was inhibited in vitro by an isoflavone genistein. The inhibition was competitive with respect to ATP and noncompetitive to a phosphate acceptor, histone H2B. By contrast, genistein scarcely inhibited the enzyme activities of serine- and threonine-specific protein kinases such as cAMP-dependent protein kinase, phosphorylase kinase, and the Ca2+/phospholipid-dependent enzyme protein kinase C. When the effect of genistein on the phosphorylation of the EGF receptor was examined in cultured A431 cells, EGF-stimulated serine, threonine, and tyrosine phosphorylation was decreased. Phosphoamino acid analysis of total cell proteins revealed that genistein inhibited the EGF-stimulated increase in phosphotyrosine level in A431 cells.
Consumption of a plant-based diet can prevent the development and progression of chronic diseases that are associated with extensive neovascularization. To determine whether prevention might be associated with dietary derived angiogenesis inhibitors, we have fractionated urine of healthy human subjects consuming a plant-based diet and examined the fractions for their abilities to inhibit the proliferation of vascular endothelial cells. One of the most potent fractions contained several isoflavonoids, which we identified by gas chromatography-mass spectrometry and subsequently synthesized. Of all synthetic compounds, the isoflavonoid genistein was the most potent and inhibited endothelial cell proliferation and in vitro angiogenesis at half maximal concentrations of 5 and 150 mumol/L, respectively. Moreover, genistein inhibited the proliferation of various tumor cells. Genistein excretion in urine of subjects consuming a plant-based diet is in the micromolar range, which is 30-fold higher than that of subjects consuming a traditional Western diet. The high concentrations of genistein in urine of vegetarians and our present results suggest that genistein may contribute to the preventive effect of plant-based diet on chronic diseases, including solid tumors, by inhibiting neovascularization and tumor cell proliferation. Thus genistein may have important applications in the treatment of solid tumors and angiogenic diseases.
Consumption of a plant-based diet can prevent the development and progression of chronic diseases associated with extensive neovascularization, including solid malignant tumors. In previous studies, we have shown that the plant-derived isoflavonoid genistein is a potent inhibitor of cell proliferation and in vitro angiogenesis. In the present study, we report that certain structurally related flavonoids are more potent inhibitors than genistein. Indeed, 3-hydroxyflavone, 3',4'-dihydroxyflavone, 2',3'-dihydroxyflavone, fisetin, apigenin, and luteolin inhibited the proliferation of normal and tumor cells, as well as in vitro angiogenesis, at half-maximal concentrations in the low micromolar range. We have previously demonstrated that genistein concentrations in the urine of subjects consuming a plant-based diet is 30-fold higher than in subjects consuming a traditional Western diet. The wider distribution and the more abundant presence of flavonoids in the plant kingdom, together with the present results, suggest that flavonoids may contribute to the preventive effect of a plant-based diet on chronic diseases, including solid tumors.
Several lines of evidence suggest that accumulation of cytoplasmic β-catenin transduces an oncogenic signal. We show that
β-catenin is ubiquitinated and degraded by the proteosome and that β-catenin stability is regulated by a diacylglycerol-independent
protein kinase C-like kinase activity, which is required for β-catenin ubiquitination. We also define a six-amino acid sequence
found in both β-catenin and the NF-κB regulatory protein IκBα, which, upon phosphorylation, targets both proteins for ubiquitination.
Mutation of a single serine within the ubiquitination targeting sequence prevents ubiquitination of β-catenin. Mutations within
the ubiquitination targeting sequence of β-catenin may be oncogenic.
Lung cancer is the leading cause of cancer-related death in the world, with increasing incidence in many developed countries. Epidemiological data suggest that consumption of soy products (the isoflavone genistein) may be associated with a decreased risk of breast and prostate cancer; however, such studies are not available for lung cancer. We investigated cell growth inhibition, modulation in gene expression, and induction of apoptosis by genistein in H460 non-small lung cancer cells. Genistein inhibited H460 cell growth in a dose-dependent manner. Flow-cytometric analysis showed that 30 microM genistein arrested cell cycle progression at the G2-M phase. 4,6-Diamidino-2-phenylindole staining, flow-cytometric analysis, and DNA laddering were used to investigate apoptotic cell death, and the results show that 30 microM genistein can cause typical DNA laddering, a hallmark for apoptosis. In addition, flow cytometry and 4,6-diamidino-2-phenylindole staining showed induction of apoptosis by genistein. Our investigation also demonstrated the modulation of p21WAF1 by Western blot analysis of cell lysates obtained from cultured cells treated with 30 and 50 microM genistein for 24, 48, and 72 hours. Simultaneously, immunocytochemical staining was conducted for the expression of p21WAF1 protein. Our results showed that genistein can upregulate p21WAF1 expression in genistein-treated cells. From these results, we conclude that genistein may act as an anticancer agent, and further studies may prove its efficacy in non-small lung cancer cells. Thus the biological effects of genistein may, indeed, be due to the modulation of cell growth, cell death, and cell cycle regulatory molecules.
The activities of cyclin D-dependent kinases serve to integrate extracellular signaling during G1 phase with the cell-cycle engine that regulates DNA replication and mitosis. Induction of D-type cyclins and their assembly into holoenzyme complexes depend on mitogen stimulation. Conversely, the fact that D-type cyclins are labile proteins guarantees that the subunit pool shrinks rapidly when cells are deprived of mitogens. Phosphorylation of cyclin D1 on a single threonine residue near the carboxyl terminus (Thr-286) positively regulates proteasomal degradation of D1. Now, we demonstrate that glycogen synthase kinase-3beta (GSK-3beta) phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclin D1 turnover. Because the activity of GSK-3beta can be inhibited by signaling through a pathway that sequentially involves Ras, phosphatidylinositol-3-OH kinase (PI3K), and protein kinase B (Akt), the turnover of cyclin D1, like its assembly, is also Ras dependent and, hence, mitogen regulated. In contrast, Ras mutants defective in PI3K signaling, or constitutively active mitogen-activated protein kinase-kinase (MEK1) mutants that act downstream of Ras to activate extracellular signal-regulated protein kinases (ERKs), cannot stabilize cyclin D1. In direct contrast to cyclin D1, which accumulates in the nucleus during G1 phase and exits into the cytoplasm during S phase, GSK-3beta is predominantly cytoplasmic during G1 phase, but a significant fraction enters the nucleus during S phase. A highly stable D1 mutant in which an alanine is substituted for the threonine at position 286 and that is refractory to phosphorylation by GSK-3beta remained in the nucleus throughout the cell cycle. Overexpression of an active, but not a kinase-defective, form of GSK-3beta in mouse fibroblasts caused a redistribution of cyclin D1 from the cell nucleus to the cytoplasm. Therefore, phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK-3beta.
Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/ threonine kinase Akt, which then phosphorylates and inactivates components of the apoptotic machinery, including BAD and Caspase 9. In this study, we demonstrate that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors. In the presence of survival factors, Akt phosphorylates FKHRL1, leading to FKHRL1's association with 14-3-3 proteins and FKHRL1's retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation, and target gene activation. Within the nucleus, FKHRL1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.
The work of Reddy et al. (S. A. Reddy, J. A. Huang, and W. S. Liao, J. Biol. Chem. 272:29167-29173, 1997) reveals that phosphatidylinositol 3-kinase (PI3K) plays a role in transducing a signal from the occupied interleukin-1 (IL-1) receptor to nuclear factor kappaB (NF-kappaB), but the underlying mechanism remains to be determined. We have found that IL-1 stimulates interaction of the IL-1 receptor accessory protein with the p85 regulatory subunit of PI3K, leading to the activation of the p110 catalytic subunit. Specific PI3K inhibitors strongly inhibit both PI3K activation and NF-kappaB-dependent gene expression but have no effect on the IL-1-stimulated degradation of IkappaBalpha, the nuclear translocation of NF-kappaB, or the ability of NF-kappaB to bind to DNA. In contrast, PI3K inhibitors block the IL-1-stimulated phosphorylation of NF-kappaB itself, especially the p65/RelA subunit. Furthermore, by using a fusion protein containing the p65/RelA transactivation domain, we found that overexpression of the p110 catalytic subunit of PI3K induces p65/RelA-mediated transactivation and that the specific PI3K inhibitor LY294,002 represses this process. Additionally, the expression of a constitutively activated form of either p110 or the PI3K-activated protein kinase Akt also induces p65/RelA-mediated transactivation. Therefore, IL-1 stimulates the PI3K-dependent phosphorylation and transactivation of NF-kappaB, a process quite distinct from the liberation of NF-kappaB from its cytoplasmic inhibitor IkappaB.
Activation of the nuclear transcription factor NF-kappaB by inflammatory cytokines requires the successive action of NF-kappaB-inducing kinase (NIK) and an IKB-kinase (IKK) complex composed of IKKalpha and IKKbeta. Here we show that the Akt serine-threonine kinase is involved in the activation of NF-kappaB by tumour necrosis factor (TNF). TNF activates phosphatidylinositol-3-OH kinase (PI(3)K) and its downstream target Akt (protein kinase B). Wortmannin (a PI(3)K inhibitor), dominant-negative PI(3)K or kinase-dead Akt inhibits TNF-mediated NF-kappaB activation. Constitutively active Akt induces NF-kappaB activity and this effect is blocked by dominant-negative NIK. Conversely, NIK activates NF-kappaB and this is blocked by kinase-dead Akt. Thus, both Akt and NIK are necessary for TNF activation of NF-kappaB. Akt mediates IKKalpha phosphorylation at threonine 23. Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF-kappaB. These findings indicate that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses.
The potential role of glycogen synthase kinase-3beta in modulating apoptosis was examined in human SH-SY5Y neuroblastoma cells. Staurosporine treatment caused time- and concentration-dependent increases in the activities of caspase-3 and caspase-9 but not caspase-1, increased proteolysis of poly(ADP-ribose) polymerase, and induced morphological changes consistent with apoptosis. Overexpression of glycogen synthase kinase-3beta to levels 3.5 times that in control cells did not alter basal indices of apoptosis but potentiated staurosporine-induced activation of caspase-3, caspase-9, proteolysis of poly(ADP-ribose) polymerase, and morphological changes indicative of apoptosis. Inhibition of glycogen synthase kinase-3beta by lithium attenuated the enhanced staurosporine-induced activation of caspase-3 in cells overexpressing glycogen synthase kinase-3beta. In cells subjected to heat shock, caspase-3 activity was more than three times greater in glycogen synthase kinase-3beta-transfected than control cells, and this potentiated response was inhibited by lithium treatment. Thus, glycogen synthase kinase-3beta facilitated apoptosis induced by two experimental paradigms. These findings indicate that glycogen synthase kinase-3beta may contribute to pro-apoptotic-signaling activity, that inhibition of glycogen synthase kinase-3beta can contribute to anti-apoptotic-signaling mechanisms, and that the neuroprotective actions of lithium may be due in part to its inhibitory modulation of glycogen synthase kinase-3beta.
Amplification or overexpression of HER-2/neu in cancer cells confers resistance to apoptosis and promotes cell growth. The cellular localization of p21Cip1/WAF1 has been proposed to be critical either in promoting cell survival or in inhibiting cell growth. Here we show that HER-2/neu-mediated cell growth requires the activation of Akt, which associates with p21Cip1/WAF1 and phosphorylates it at threonine 145, resulting in cytoplasmic localization of p21Cip1/WAF1. Furthermore, blocking the Akt pathway with a dominant-negative Akt mutant restores the nuclear localization and cell-growth-inhibiting activity of p21Cip1/WAF1. Our results indicate that HER-2/neu induces cytoplasmic localization of p21Cip1/WAF1 through activation of Akt to promote cell growth, which may have implications for the oncogenic activity of HER-2/neu and Akt.
Protein-tyrosine kinases (PTKs) are important regulators of intracellular signal-transduction pathways mediating development and multicellular communication in metazoans. Their activity is normally tightly controlled and regulated. Perturbation of PTK signalling by mutations and other genetic alterations results in deregulated kinase activity and malignant transformation. The lipid kinase phosphoinositide 3-OH kinase (PI(3)K) and some of its downstream targets, such as the protein-serine/threonine kinases Akt and p70 S6 kinase (p70S6K), are crucial effectors in oncogenic PTK signalling. This review emphasizes how oncogenic conversion of protein kinases results from perturbation of the normal autoinhibitory constraints on kinase activity and provides an update on our knowledge about the role of deregulated PI(3)K/Akt and mammalian target of rapamycin/p70S6K signalling in human malignancies.
The nuclear expression and action of the nuclear factor kappa B (NF-κB) transcription factor requires signal-coupled phosphorylation
and degradation of the IκB inhibitors, which normally bind and sequester this pleiotropically active factor in the cytoplasm.
The subsequent molecular events that regulate the termination of nuclear NF-κB action remain poorly defined, although the
activation of de novo IκBα gene expression by NF-κB likely plays a key role. Our studies now demonstrate that the RelA subunit
of NF-κB is subject to inducible acetylation and that acetylated forms of RelA interact weakly, if at all, with IκBα. Acetylated
RelA is subsequently deacetylated through a specific interaction with histone deacetylase 3 (HDAC3). This deacetylation reaction
promotes effective binding to IκBα and leads in turn to IκBα-dependent nuclear export of the complex through a chromosomal
region maintenance-1 (CRM-1)–dependent pathway. Deacetylation of RelA by HDAC3 thus acts as an intranuclear molecular switch
that both controls the duration of the NF-κB transcriptional response and contributes to the replenishment of the depleted
cytoplasmic pool of latent NF-κB–IκBα complexes.
The ubiquitously expressed transcription factor NF-κB and the serine-threonine kinase Akt both are involved in the promotion
of cell survival. Although initially believed to operate as components of distinct signaling pathways, several studies have
demonstrated that the NF-κB and Akt signaling pathways can converge. Indeed, IκB kinase, the kinase involved in NF-κB activation,
is a substrate of Akt, and activation of Akt therefore stimulates NF-κB activity. Although these results place Akt upstream
of NF-κB activation in the sequence of signaling events, we report that this may not necessarily be the case and that Akt
is a downstream target of NF-κB. Treatment of NIH3T3 cells with the NF-κB activators, tumor necrosis factor (TNF) α and lipopolysaccharide,
results in the stimulation of Akt phosphorylation. The stimulation of Akt is, however, detected only after IκB-α degradation
is induced by these agents. The nuclear translocation of p65 and increased DNA binding activity of NF-κB also precede Akt
phosphorylation. Treatment with two pharmacological inhibitors of NF-κB, SN50 andN-tosyl-l-phenylalanine chloromethyl ketone (TPCK), blocks TNF-induced Akt activation. On the other hand TNF-mediated NF-κB activation
is not reduced by the phosphoinositide-3 kinase inhibitors wortmannin and LY294002, although these inhibitors completely block
the activation of Akt. These results suggest that NF-κB is required for TNF-mediated Akt activation and that it lies upstream
of the stimulation of Akt. Consistent with this conclusion is the finding that overexpression of p65/RelA leads to Akt phosphorylation
in the absence of extracellular stimulatory factors, whereas overexpression of IκB-α reduces Akt phosphorylation below basal
levels. Interestingly, in addition to stimulating the phosphorylation of Akt, overexpression of p65 causes an increase in
the expression of Akt mRNA and protein.
PI3K/Akt plays a critical role in prostate cancer cell growth and survival. Recent studies have shown that the effect of PI3K/Akt
in prostate cells is mediated through androgen signaling. The PI3K inhibitor, LY294002, and a tumor suppressor, PTEN, negatively
regulate the PI3K/Akt pathway and repress AR activity. However, the molecular mechanisms whereby PI3K/Akt and PTEN regulate
the androgen pathway are currently unclear. Here, we demonstrate that blocking the PI3K/Akt pathway reduces the expression
of an endogenous AR target gene. Moreover, we show that the repression of AR activity by LY294002 is mediated through phosphorylation
and inactivation of GSK3β, a downstream substrate of PI3K/Akt, which results in the nuclear accumulation of β-catenin. Given
the recent evidence that β-catenin acts as a coactivator of AR, our findings suggest a novel mechanism by which PI3K/Akt modulates
androgen signaling. In a PTEN-null prostate cancer cell line, we show that PTEN expression reduces β-catenin-mediated augmentation
of AR transactivation. Using the mutants of β-catenin, we further demonstrate that the repressive effect of PTEN is mediated
by a GSK3β-regulated degradation of β-catenin. Our results delineate a novel link among the PI3K, wnt, and androgen pathways
and provide fresh insights into the mechanisms of prostate tumor development and progression.
The cyclin-dependent kinase inhibitor p27(kip1) is a putative tumor suppressor for human cancer. The mechanism underlying p27(kip1) deregulation in human cancer is, however, poorly understood. We demonstrate that the serine/threonine kinase Akt regulates cell proliferation in breast cancer cells by preventing p27(kip1)-mediated growth arrest. Threonine 157 (T157), which maps within the nuclear localization signal of p27(kip1), is a predicted Akt-phosphorylation site. Akt-induced T157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced G1 arrest. Conversely, the p27(kip1)-T157A mutant accumulates in cell nuclei and Akt does not affect p27(kip1)-T157A-mediated cell cycle arrest. Lastly, T157-phosphorylated p27(kip1) accumulates in the cytoplasm of primary human breast cancer cells coincident with Akt activation. Thus, cytoplasmic relocalization of p27(kip1), secondary to Akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained.
Mechanisms linking mitogenic and growth inhibitory cytokine signaling and the cell cycle have not been fully elucidated in either cancer or in normal cells. Here we show that activation of protein kinase B (PKB)/Akt, contributes to resistance to antiproliferative signals and breast cancer progression in part by impairing the nuclear import and action of p27. Akt transfection caused cytoplasmic p27 accumulation and resistance to cytokine-mediated G1 arrest. The nuclear localization signal of p27 contains an Akt consensus site at threonine 157, and p27 phosphorylation by Akt impaired its nuclear import in vitro. Akt phosphorylated wild-type p27 but not p27T157A. In cells transfected with constitutively active Akt(T308DS473D)(PKB(DD)), p27WT mislocalized to the cytoplasm, but p27T157A was nuclear. In cells with activated Akt, p27WT failed to cause G1 arrest, while the antiproliferative effect of p27T157A was not impaired. Cytoplasmic p27 was seen in 41% (52 of 128) of primary human breast cancers in conjunction with Akt activation and was correlated with a poor patient prognosis. Thus, we show a novel mechanism whereby Akt impairs p27 function that is associated with an aggressive phenotype in human breast cancer.
Flavonoids, such as daidzein and genistein, present in dietary plants like soybean, have unique chemical properties with biological activity relevant to cancer. Many flavonoids and polyphenols, including resveratrol in red wine and epigallocatechin gallate in green tea, are known antioxidants. Some of these compounds have estrogenic (and antiestrogenic) activity and are commonly referred to as phytoestrogens. A yeast-based estrogen receptor (ER) reporter assay has been used to measure the ability of flavonoids to bind to ER and activate estrogen responsive genes. Recently, estrogenic compounds were also shown to trigger rapid, nongenomic effects. The molecular mechanisms, however, have not been completely detailed and little information exists regarding their relevance to cancer progression. As a preliminary step toward elucidating rapid phytoestrogen action on breast cancer cells, we investigated the effect of 17-β estradiol (E2), genistein, daidzein and resveratrol on the activation status of signaling proteins that regulate cell survival and invasion, the cell properties underlying breast cancer progression. The effect of these estrogenic compounds on the activation, via phosphorylation, of Akt/protein kinase B (Akt) and focal adhesion kinase (FAK) were analyzed in ER-positive and -negative human breast cancer cell lines. E2, genistein and daidzein increased whereas resveratrol decreased both Akt and FAK phosphorylation in nonmetastatic ER-positive T47D cells. In metastatic ER-negative MDA-MB-231 cells, all estrogenic compounds tested increased Akt and FAK phosphorylation. The inhibitory action of resveratrol on cell survival and proliferation is ER dependent. Therefore, all estrogenic compounds tested, including resveratrol, may exert supplementary ER-independent nongenomic effects on cell survival and migration in breast cancer cells.
This chapter highlights NF-кB/Rel protein complex. Associations of the binding and regulatory subunits of NF-кB operate at the center of a variety of different signal pathways. NF-кB can process and integrate instructions that come from the extracellular environment and detect intracellular events originating in either the cytoplasm or the nucleus. NF-кB then transmits this information with astonishing rapidity to the transcriptional machinery by directly binding to a range of different DNA sequences in gene control regions. NF-кB comprises members of a family of dimer-forming proteins with homology to the rel oncogene. NF-кB has the striking appearance of being constitutively present only in B cells of the “appropriate” stage for Ig к light chain gene expression. The functional role of NF-кB is demonstrated by mutational analysis of the к intronic enhancer. The property that gives NF-кB a widespread significance in cellular regulation is its role as a mediator of inducible gene transcription. The key features of NF-кB transcriptional control are that it is fast and versatile and is used in many different gene systems. It also has the important ability to carry signals from the cytoplasm into the nucleus and trans-activate specific genes by binding directly to their promoters.
Signal-induced activation of the transcription factor NF-κB requires specific phosphorylation of the inhibitor IκBα and its subsequent proteolytic degradation. Phosphorylation of serine residues 32 and 36 targets IκBα to the ubiquitin (Ub)–proteasome pathway. Here we report the identification of a large, multisubunit kinase (molecular mass ∼700 kDa) that phosphorylates IκBα at S32 and S36. Remarkably, the activity of this kinase requires the Ub-activating enzyme (E1), a specific Ub carrier protein (E2) of the Ubc4/Ubc5 family, and Ub. We also show that a ubiquitination event in the kinase complex is a prerequisite for specific phosphorylation of IκBα. Thus, ubiquitination serves a novel regulatory function that does not involve proteolysis.
Genistein, a natural isoflavonoid phytoestrogen, is a strong inhibitor of protein tyrosine kinases. We analyzed the effects of genistein on in vitro growth, cell-cycle progression and chromatin structure of Jurkat cells, a T-cell leukemia line with a constitutively increased tyrosine phosphorylation pattern. Exposure of in vitro cultured Jurkat cells to genistein resulted in a dose-dependent, growth inhibition. Cell-cycle analysis of genistein-treated cells revealed a G2/M arrest at low genistein concentrations (5–10 μg/ml), while at higher doses (20–30 μg/ml) there was also a perturbation in S-phase progression. The derangements in cell-cycle control were followed by apoptosic death of genistein-treated cells. Immunocytochemical analysis of cells stained with a FITC-conjugated anti-phosphotyrosine monoclonal antibody showed that 30 μ/ml genistein effectively inhibit tyrosine kinase activity in cultured Jurkat cells. Our results indicate that the natural isoflavone genistein antagonizes tumor cell growth through both cell-cycle arrest and induction of apoptosis and suggest that it could be a promising new agent in cancer therapy.
Recent evidence indicates that the transcription factor NF-κB is a major effector of inducible antiapoptotic mechanisms. For example, it was shown that NF-κB activation suppresses the activation of caspase 8, the apical caspase in tumor necrosis factor (TNF) receptor family signaling cascades, through the transcriptional regulation of certain TRAF and IAP proteins. However, it was unknown whether NF-κB controls other key regulatory mechanisms in apoptosis. Here we show that NF-κB activation suppresses mitochondrial release of cytochrome
c
through the activation of the Bcl-2 family member A1/Bfl-1. The restoration of A1 in NF-κB null cells diminished TNF-induced apoptosis by reducing the release of proapoptotic cytochrome
c
from mitochondria. In addition, A1 potently inhibited etoposide-induced apoptosis by inhibiting the release of cytochrome
c
and by blocking caspase 3 activation. Our findings demonstrate that A1 is an important antiapoptotic gene controlled by NF-κB and establish that the prosurvival function of NF-κB can be manifested at multiple levels.
PTEN/MMAC1 is a tumor suppressor gene located on chromosome 10q23. Inherited PTEN/MMAC1 mutations are associated with a cancer predisposition syndrome known as Cowden’s disease. Somatic mutation of PTEN has been found in a number of malignancies, including glioblastoma, melanoma, and carcinoma of the prostate and endometrium. The protein product (PTEN) encodes a dual-specificity protein phosphatase and in addition can dephosphorylate certain lipid substrates. Herein, we show that PTEN protein induces a G1 block when reconstituted in PTEN-null cells. A PTEN mutant associated with Cowden’s disease (PTEN;G129E) has protein phosphatase activity yet is defective in dephosphorylating inositol 1,3,4,5-tetrakisphosphate in vitro and fails to arrest cells in G1. These data suggest a link between induction of a cell-cycle block by PTEN and its ability to dephosphorylate, in vivo, phosphatidylinositol 3,4,5-trisphosphate. In keeping with this notion, PTEN can inhibit the phosphatidylinositol 3,4,5-trisphosphate-dependent Akt kinase, a downstream target of phosphatidylinositol 3-kinase, and constitutively active, but not wild-type, Akt overrides a PTEN G1 arrest. Finally, tumor cells lacking PTEN contain high levels of activated Akt, suggesting that PTEN is necessary for the appropriate regulation of the phosphatidylinositol 3-kinase/Akt pathway.
Breast cancer is still relatively infrequent in Japan. However, both mortality and morbidity rates have sharply increased in recent years, especially in ages 45–59. The risk was noted to be 8.5 times higher in women of high socioeconomic strata eating meat daily compared with women of low socioeconomic strata who do not eat meat daily, when 142,857 women aged 40 years were followed for 10 years. A high positive correlation was found between per capita fat intake and adjusted death rates of breast cancer in different districts of Japan. It was estimated that the breast cancer death rate will rise to the U.S. level when Japanese dietary fat intake approaches present day U.S. levels. The close correlation with fat intake was noted to come mainly from the consumption of pork and animal fat. The ratio of recent increase in breast cancer death rates was also found to be under the combined influence of animal fat and AF2, a highly mutagenic food additive widely used in Japan from 1965 to 1975 and shown to produce mammary carcinoma in rats. A series of case-control studies reveals the higher risk of breast cancer with the increase in body size especially in postmenopausal women. The recent breast cancer increase could therefore be a reflection of the fact that women in Japan are becoming heavier, especially after age 30.
International differences in breast cancer morbidity and mortality and studies on migrating populations point to the overriding importance of environmental factors in the etiology of breast cancer. Factors directly or indirectly associated with ovarian activity do not appear to explain international differences. Population correlation studies have indicated that much of the difference appears to be explicable on the basis of nutritional factors, particularly, high total fat intake. Animal experimental studies confirm the importance of high fat diet, possibly mediated through prolactin. Other indirect support for the nutritional hypothesis is supplied by changing incidence rates in Iceland, possibly correlated with changing nutritional practices and the association of breast cancer with weight and possibly also with height. The association with height (which would suggest nutritional effects mediated through childhood diet) has not been supported by a study in Canada. Direct investigation of the association between nutrition and breast cancer is difficult because of problems in dietary methodology. Nevertheless, the results of a Canadian case-control study provide support for the importance of high fat intake. Further studies of this question are undoubtedly required, however, before specific recommendations on dietary modification can be made.
Mortality studies for the period around 1950 and 1960 showed breast cancer mortality rates of Japanese American women only slightly above levels prevailing in Japan, though other site specific cancer risks had shifted more markedly toward levels of white Americans. The Third National Cancer Survey of 1969-71 reveals that breast cancer risks for Japanese American women in the San Francisco Oakland metropolitan area closely approached those for whites. This upward shift occurred among both the Nisei (second generation) and the Issei (immigrant generation). The contribution of the Issei to the increased rates was substantial but somewhat less than that of the Nisei. Although Japanese and Polish migrants arrived in the United States about the same time, and both were mainly of rural origin, only the Polish women demonstrated a substantially increased risk of breast cancer by 1950. Japanese migrants may have retained their traditional culture longer, and when the strong upward shift in breast cancer risk occurred, it did so among Japanese American women potentially exposed to a new culture and environment at preadult and early adult ages.
NF-kappa B, which consists of two polypeptides, p50 (M(r) 50K) and p65/RelA (M(r) 65K), is thought to be a key regulator of genes involved in responses to infection, inflammation and stress. Indeed, although developmentally normal, mice deficient in p50 display functional defects in immune responses. Here we describe the generation of mice deficient in the RelA subunit of NF-kappa B. Disruption of the relA locus leads to embryonic lethality at 15-16 days of gestation, concomitant with a massive degeneration of the liver by programmed cell death or apoptosis. Embryonic fibroblasts from RelA-deficient mice are defective in the tumour necrosis factor (TNF)-mediated induction of messenger RNAs for I kappa B alpha and granulocyte/macrophage colony stimulating factor (GM-CSF), although basal levels of these transcripts are unaltered. These results indicate that RelA controls inducible, but not basal, transcription in NF-kappa B-regulated pathways.
We have investigated the potential of genistein, an estrogenic component of soy, when administered neonatally, to manifest a protective effect against chemically induced mammary cancer. Female Sprague-Dawley rats were treated on Day 2, 4, and 6 postpartum with genistein or dimethylsulfoxide (vehicle). To induce mammary carcinogenesis, all animals were subsequently exposed on Day 50 postpartum to dimethylbenz(a)anthracene. Animals treated neonatally with genistein had increased latency and reduced incidence and multiplicity of mammary tumors compared with vehicle-treated animals. Cell differentiation studies in mammary whole mounts revealed that neonatal genistein treatment resulted in decreased numbers of terminal end buds and increased numbers of lobular structures. A precocious maturation of undifferentiated terminal end buds to more differentiated lobules may account for neonatal genistein treatment protecting against chemically induced mammary cancer.
Here we report that genistein, a soybean isoflavone, strongly inhibits tumor promoter-induced H2O2 formation both in vivo and in vitro. Genistein suppressed H2O2 production by 12-O-tetradecanoylphorbol-13-acetate- (TPA) stimulated human polymorphonuclear leukocytes (PMNs) and HL-60 cells in a dose-dependent manner over the concentration range 1-150 microM. Human PMNs were more sensitive to the inhibitory effect of genistein than HL-60 cells (50% inhibitory concentration 14.8 and 30.2 microM, respectively). In addition, genistein moderately inhibited superoxide anion formation by HL-60 cells and scavenged exogenously added H2O2 under the same conditions as in cell culture. However, the H2O2-scavenging effect of genistein was about 50% lower than its inhibition of cell-derived H2O2 formation at all concentrations. In the CD-1 mouse skin model, genistein strongly inhibited TPA-induced oxidant formation, edema, and PMN infiltration in mouse skin. Inhibition of TPA-mediated H2O2 in vivo may result from decreased cell-derived H2O2 formation, scavenging of H2O2 produced, and/or suppression of PMN infiltration into the dermis. The antioxidant properties of genistein may be responsible for its anticarcinogenic effects, and the dietary availability of genistein makes it a promising candidate for the prevention of human cancers.
Tumor necrosis factor α (TNF-α) signaling gives rise to a number of events, including activation of transcription factor NF-κB
and programmed cell death (apoptosis). Previous studies of TNF-α signaling have suggested that these two events occur independently.
The sensitivity and kinetics of TNF-α-induced apoptosis are shown to be enhanced in a number of cell types expressing a dominant-negative
IκBα (IκBαM). These findings suggest that a negative feedback mechanism results from TNF-α signaling in which NF-κB activation
suppresses the signals for cell death.
Insulin activated endogenous protein kinase B alpha (also known as RAC/Akt kinase) activity 12-fold in L6 myotubes, while after transfection into 293 cells PKBalpha was activated 20- and 50-fold in response to insulin and IGF-1 respectively. In both cells, the activation of PKBalpha was accompanied by its phosphorylation at Thr308 and Ser473 and, like activation, phosphorylation of both of these residues was prevented by the phosphatidylinositol 3-kinase inhibitor wortmannin. Thr308 and/or Ser473 were mutated to Ala or Asp and activities of mutant PKBalpha molecules were analysed after transfection into 293 cells. The activity of wild-type and mutant PKBalpha was also measured in vitro after stoichiometric phosphorylation of Ser473 by MAPKAP kinase-2. These experiments demonstrated that activation of PKBalpha by insulin or insulin-like growth factor-1 (IGF-1) results from phosphorylation of both Thr308 and Ser473, that phosphorylation of both residues is critical to generate a high level of PKBalpha activity and that the phosphorylation of Thr308 in vivo is not dependent on phosphorylation of Ser473 or vice versa. We propose a model whereby PKBalpha becomes phosphorylated and activated in insulin/IGF-1-stimulated cells by an upstream kinase(s).
Protein kinase B (PKB)/Akt is a growth-factor-regulated serine/threonine kinase which contains a pleckstrin homology domain. Binding of phosphoinositide 3-OH kinase products to the pleckstrin homology domain results in translocation of PKB/Akt to the plasma membrane where it is activated by phosphorylation by upstream kinases including the phosphoinoside-dependent kinase 1 (PDK1). Activated PKB/Akt provides a survival signal that protects cells from apoptosis induced by various stresses, and also mediates a number of metabolic effects of insulin.
Tumor necrosis factor α (TNF-α) binding to the TNF receptor (TNFR) potentially initiates apoptosis and activates the transcription
factor nuclear factor kappa B (NF-κB), which suppresses apoptosis by an unknown mechanism. The activation of NF-κB was found
to block the activation of caspase-8. TRAF1 (TNFR-associated factor 1), TRAF2, and the inhibitor-of-apoptosis (IAP) proteins
c-IAP1 and c-IAP2 were identified as gene targets of NF-κB transcriptional activity. In cells in which NF-κB was inactive,
all of these proteins were required to fully suppress TNF-induced apoptosis, whereas c-IAP1 and c-IAP2 were sufficient to
suppress etoposide-induced apoptosis. Thus, NF-κB activates a group of gene products that function cooperatively at the earliest
checkpoint to suppress TNF-α–mediated apoptosis and that function more distally to suppress genotoxic agent–mediated apoptosis.
Dietary genistein, a natural flavone compound found in soy, has been proposed to be responsible for the low rate of breast cancer in Asian women. The cellular mechanisms of genistein's chemopreventive effects in vio have been largely unexplored. In our previous studies, we found that genistein exerted pronounced antiproliferative effects on both estrogen receptor-positive and -negative human breast carcinoma cells through G2-M arrest, induction of p21WAF1/CIP1 expression, and apoptosis. Because chemopreventive effects need not be limited to antiproliferation, we decided to examine whether genistein exerted other suppressive effects on breast carcinoma progression. Genistein inhibited invasion in vitro of MCF-7 and MDA-MB-231 cells. This inhibition was characterized by down-regulation of MMP (matrix metalloproteinase)-9 and up-regulation of tissue inhibitor of metalloproteinase-1, the former of which was transcriptionally regulated at activation protein-1 sites in the MMP-9 promoter. Genistein's in vitro effects on MMP-9 and tissue inhibitor of metalloproteinase-1 were also demonstrated in in vivo studies in nude mouse xenografts of MDA-MB-231 and MCF-7 cells. In these xenograft studies, genistein inhibited tumor growth, stimulated apoptosis, and upregulated p21WAF1/CIP1 expression. In the MDA-MB-231 xenograft, genistein also inhibited angiogenesis by decreasing vessel density and decreasing the levels of vascular endothelial growth factor and transforming growth factor-beta1. These in vitro and in vivo studies demonstrate that genistein exerts multiple suppressive effects on breast carcinoma cells, suggesting that its mechanism of chemoprevention is pleiotropic.
Increased soy consumption in Asian diets, resulting in increased serum isoflavone levels, has been associated with a decreased risk for prostate adenocarcinoma (PCa). The isoflavone genistein is believed to be the anticancer agent found in soy, and significant levels of genistein have been detected in human prostatic fluid, implicating the role of genistein in PCa prevention. Recent studies have demonstrated genistein's ability to inhibit cell growth and induce apoptosis in several cell lines; however, the molecular mechanisms of genistein's effect are not known. We have evaluated the mechanism by which genistein may inhibit PCa cell growth. Here we report that genistein inhibits PCa cell growth in culture in a dose-dependent manner, which is accompanied by a G2/M cell cycle arrest. Cell growth inhibition was observed with concomitant downregulation of cyclin B, upregulation of the p21WAF1 growth-inhibitory protein, and induction of apoptosis. Collectively, these results provide experimental evidence for a novel effect of genistein on cell cycle gene regulation, resulting in the inhibition of cell growth and ultimate demise of tumor cells.
Breast cancer is the most common cancer among American women, whereas Asian women, who consume a traditional diet high in soy products, have a relatively low incidence. Genistein is a prominent isoflavonoid in soy products and has been proposed as the agent responsible for lowering the rate of breast cancer in Asian women. We investigated the effects of genistein on cell growth and apoptosis-related gene expression in breast cancer cells MDA-MB-231. We found up-regulation of Bax and p21WAF1 expressions and down-regulation of Bcl-2 and p53 expression in genistein-treated cells. Furthermore, DNA ladder formation, CPP32 activation, and PARP cleavage were observed after treatment with genistein, indicating apoptotic cell deaths. Flow cytometry with 7-amino actinomycin D staining showed that the number of apoptotic cells increased with longer treatment of genistein. From these results, we conclude that genistein inhibits the growth of MDA-MB-231 breast cancer cells, regulates the expression of apoptosis-related genes, and induces apoptosis through a p53-independent pathway. The up-regulation of Bax and p21WAF1 may be the molecular mechanisms by which genistein induces apoptosis, however, further definitive studies are needed. These results suggest that genistein may be a potentially effective chemopreventive or therapeutic agent against breast cancer.
The serine/threonine kinase Akt (also known as protein kinase B, PKB) is activated by numerous growth-factor and immune receptors through lipid products of phosphatidylinositol (PI) 3-kinase. Akt can couple to pathways that regulate glucose metabolism or cell survival [1]. Akt can also regulate several transcription factors, including E2F, CREB, and the Forkhead family member Daf-16 [2] [3] [4]. Here, we show that Akt can regulate signaling pathways that lead to induction of the NF-kappaB family of transcription factors in the Jurkat T-cell line. This induction occurs, at least in part, at the level of degradation of the NF-kappaB inhibitor IkappaB, and is specific for NF-kappaB, as other inducible transcription factors are not affected by Akt overexpression. Furthermore, the effect requires the kinase activity and pleckstrin homology (PH) domain of Akt. Also, Akt does not act alone to induce cytokine promoters and NF-kappaB reporters, because signals from other pathways are required to observe the effect. These studies uncover a previously unappreciated connection between Akt and NF-kappaB induction that could have implications for the control of T-cell growth and survival.
Breast cancer is the most common cancer and second leading cause of cancer related deaths in women in the United States. Genistein is a protein tyrosine kinase inhibitor and prominent isoflavonoid in soy products and has been proposed as the agent responsible for lowering the rate of breast cancer in Asian women. We have previously shown that genistein inhibits the growth of MDA-MB-231 breast cancer cells, regulates the expression of apoptosis-related genes, and induces apoptosis through a p53-independent pathway. In this study, we investigated these effects of genistein in the breast cancer cell line MDA-MB-435 and 435.eB cells that were established by transfecting c-erbB-2 cDNA into MDA-MB-435. We also investigated the effect of genistein on matrix metalloproteinase (MMP) secretion previously shown to be effected by erbB-2 transfection. Genistein was found to inhibit MDA-MB-435 and 435.eB cell growth. Induction of apoptosis was also observed in these cell lines when treated with genistein, as measured by DNA laddering, poly(ADP-ribose) polymerase (PARP) cleavage, and flow cytometric analysis. We also found an up-regulation of Bax and p21WAF1 expression and down-regulation of Bcl-2 and c-erbB-2 in genistein-treated cells. Gelatin zymography showed that genistein inhibits the secretion of MMP in the breast cancer cells. From these results, we conclude that genistein inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and may inhibit invasion and metastasis of breast cancer cells. These findings suggest that genistein may be a potentially effective chemopreventive or therapeutic agent against breast cancer.
Members of the Wnt family of secreted glycoproteins participate in many signalling events during development. Recent findings suggest that Wnt signals can sometimes play a permissive role during cell-fate assignment. Wnt proteins have been shown to interact with a number of extracellular and cell-surface proteins, whereas many intracellular components of the Wnt-signalling pathway are also involved in other cellular functions. The consequences of Wnt signalling can be affected by members of the MAP kinase family. These observations suggest that the future understanding of Wnt signalling may require models that are based on a signalling network rather than a single linear pathway.
Epidemiological studies have shown a lower incidence of breast, prostate, and colon cancers in Asian countries, particularly China and Japan, than in the United States. It is believed that genistein, a natural tyrosine kinase inhibitor and a metabolite of soy products, may be responsible for the protection from these cancers. Genistein was shown to inhibit cell proliferation and to induce cell cycle arrest at the G2-M phase in breast, prostate, and jurkat T cell leukemia cell lines. However, such studies have not been reported in squamous cell cancers of the head and neck. In this report, we show that genistein inhibits proliferation of a squamous cell carcinoma cell line HN4. Additionally, genistein caused cell cycle arrest at the S/G2-M phase and induced programmed cell death (apoptosis) in these cells. These effects appear to be dose and time dependent, irreversible, persisting when the cells were recultured in genistein-free medium for up to 72 hours, and specific for tumor cells, because genistein did not affect normal keratinocytes. These results suggest that if genistein shows similar results in clinical trials, it can be a potential chemopreventive/chemotherapeutic agent for cancers of the head and neck.
The mechanisms of cell proliferation and transformation are intrinsically linked to the process of apoptosis: the default of proliferating cells is to die unless specific survival signals are provided. Platelet-derived growth factor (PDGF) is a principal survival factor that inhibits apoptosis and promotes proliferation, but the mechanisms mediating its anti-apoptotic properties are not completely understood. Here we show that the transcription factor NF-kappaB is important in PDGF signalling. NF-kappaB transmits two signals: one is required for the induction of proto-oncogene c-myc and proliferation, and the second, an anti-apoptotic signal, counterbalances c-Myc cytotoxicity. We have traced a putative pathway whereby PDGF activates NF-kappaB through Ras and phospatidylinositol-3-kinase (PI(3)K) to the PKB/Akt protein kinase and the IkappaB kinase (IKK); NF-kappaB thus appears to be a target of the anti-apoptotic Ras/PI(3)K/Akt pathway. We show that, upon PDGF stimulation, Akt transiently associates in vivo with IKK and induces IKK activation. These findings establish a role for NF-kappaB in growth factor signalling and define an anti-apoptotic Ras/PI(3)K/Akt/IKK/NF-kappaB pathway, thus linking anti-apoptotic signalling with transcription machinery.
Transforming growth factor-beta 1 (TGF-beta 1) stimulates migration/invasion of mouse transformed keratinocytes and increases urokinase (u-PA) expression/secretion. In this report, we analyzed the biological behavior of two naturally occurring inhibitors of protein tyrosine kinases, genistein and curcumin, that could abrogate the enhancement of u-PA levels induced by TGF-beta 1 in transformed keratinocytes. Our results showed that genistein and curcumin blocked this response in a dose-dependent manner and also inhibited the TGF-beta 1-induced synthesis of fibronectin, an early responsive gene to the growth factor. Both compounds also reduced TGF-beta 1-stimulated cell migration and invasiveness. These results suggest that a tyrosine kinase-signaling pathway should be involved in TGF-beta 1-mediated increased malignancy of transformed keratinocytes and that genistein and curcumin could play an important role in inhibiting tumor progression.
HER-2/neu amplification or overexpression can make cancer cells resistant to apoptosis and promotes their growth. p53 is crucial in regulating cell growth and apoptosis, and is often mutated or deleted in many types of tumour. Moreover, many tumours with a wild-type gene for p53 do not have normal p53 function, suggesting that some oncogenic signals suppress the function of p53. In this study, we show that HER-2/neu-mediated resistance to DNA-damaging agents requires the activation of Akt, which enhances MDM2-mediated ubiquitination and degradation of p53. Akt physically associates with MDM2 and phosphorylates it at Ser166 and Ser186. Phosphorylation of MDM2 enhances its nuclear localization and its interaction with p300, and inhibits its interaction with p19ARF, thus increasing p53 degradation. Our study indicates that blocking the Akt pathway mediated by HER-2/neu would increase the cytotoxic effect of DNA-damaging drugs in tumour cells with wild-type p53.
The preponderance of evidence suggests a role for fat and alcohol as risk factors for breast cancer. The role of milk is more controversial with some studies suggesting that milk is a risk factor and others that consumption of milk is protective against breast cancer. No other major nutrient appears to play a significant role in increasing breast cancer risk. On the other hand, there is increasing evidence that a variety of micronutrients and hormones appear to have significant anticancer activity. These range from steroids such as dehydroepiandrosterone (DHEA) and its analysis to indoles, isothiocyanates, and isoflavone derivatives. These compounds act directly by interfering with cyclins and promoting apoptosis as well as indirectly by altering estrogen metabolism in a favorable direction. These effects are not merely theoretical actions in cell culture and tissue explants; they have been demonstrated in human patients as a range of studies have demonstrated.
Prostate cancer is the second leading cause of cancer-related deaths in menin the United States. Genistein is a prominent isoflavonoid found in soy products and has been proposed to be responsible for lowering the rate of prostate cancer in Asians. However, the molecular mechanism(s) by which genistein elicits its effects on prostate cancer cells has not been fully elucidated. We have previously shown that genistein induces apoptosis and inhibits the activation of nuclear factor kappaB (NF-kappaB) pathway, which could be mediated via Akt signaling pathway, the most important survival pathway in cellular signaling. In this study, we investigated whether there is any cross-talk between Akt and NF-kappaB during genistein-induced apoptosis in PC3 prostate cancer cells. We found that genistein inhibits cell growth and induces apoptotic processes in PC3 prostate cancer cells but not in nontumorigenic CRL-2221 human prostate epithelial cells. Immunoprecipitation, kinase assays, and Western blot analysis showed that genistein specifically inhibits Akt kinase activity and abrogates the epidermal growth factor-induced activation of Akt in prostate cancer cells. NF-kappaB DNA-binding analysis and transfection studies with Akt cDNA and NF-kappaB-Luc constructs revealed that Akt transfection results in the induction of NF-kappaB activation and this is completely inhibited by genistein treatment. Moreover, genistein abrogated the epidermal growth factor-induced activation of NF-kappaB, which was mediated via Akt signaling pathway. From these results, we conclude that the inhibition of Akt and NF-kappaB activity and their cross-talk provide a novel mechanism by which genistein inhibits cell growth and induces apoptotic processes in tumorigenic but not in nontumorigenic prostate epithelial cells.
Cancer is a hyperproliferative disorder in which invasion and angiogenesis lead to tumor metastasis. Several genes that mediate tumorigenesis and metastasis are regulated by a nuclear transcription factor, nuclear factor kappa B (NF-kappaB). A heterotrimeric complex consisting of p50, p65, and IkappaBalpha, NF-kappaB is present in its inactive state in the cytoplasm. When NF-kappaB is activated, IkappaBalpha is degraded and p50-p65 heterodimer is translocated to the nucleus, binds the DNA (at the promoter region), and activates gene. Research within the last few years has revealed that NF-kappaB is activated by carcinogens, tumor promoters, inflammatory cytokines, and by chemotherapeutic agents. The activation of NF-kappaB can suppress apoptosis, thus promoting chemoresistance and tumorigenesis. Interestingly, however, most chemopreventive agents appear to suppress the activation of the NF-kappaB through inhibition of NF-kappaB signaling pathway. These chemopreventive agents also sensitize the tumors to chemotherapeutic agents through abrogation of NF-kappaB activation. Overall, these observations suggest that NF-kappaB is an ideal target for chemoprevention and chemosensitization. This article reviews evidence supporting this hypothesis.