Article

Peonidin 3-Glucoside Inhibits Lung Cancer Metastasis by Downregulation of Proteinases Activities and MAPK Pathway

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Abstract

Anthocyanins, present in various vegetables and fruits as a nature colorant, have broad activities including anticarcinogenesis and antimutagenesis, which are generally attributed to their antioxidant activities. However, limited studies have been available concerning the inhibitory effect of peonidin 3-glucoside (P3G) for cancer metastasis. Here, we demonstrated that P3G could significantly inhibit the invasion (P < 0.001), motility (P < 0.05), secretion of matrix metalloproteinase (MMP)-2, MMP-9, and urokinase-type plasminogen activator (u-PA) of lung cancer cells. Meanwhile, P3G attenuated phosphorylation of extracellular signal-regulated kinase (ERK)1/2, a member of mitogen-activated protein kinase (MAPK) family involved in the upregulation of MMPs and u-PA, and also inhibited the activation of activating protein-1 (AP-1) as shown by Western blot and electrophoretic mobility shift assay. Thus, the inhibitory effects of P3G may be at least partly through inactivation of ERK 1/2 and AP-1 signaling pathways as confirmed by abolishment of P3G-inhibited H1299 cell invasion by overexpression of MAPK kinase 1 (MEK1). Finally, P3G was evidenced by its inhibition on the metastasis of Lewis lung carcinoma cells in vivo (P < 0.001). Taken together, these findings suggested that P3G could reduce the metastasis of lung cancer cells, thereby constituting an adjuvant treatment for metastasis control.

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... Flavonoids, including anthocyanins, have attracted much attention for the potential health benefits in obesity control (Prior et al., 2008), diabetes control (Wedick et al., 2012), cardiovascular disease (CVD) prevention ( Van et al., 2013), visual (Shim et al., 2012) and brain function (Gutierres et al., 2012) improvement, mainly due to its anti-inflammatory, antioxidant and chemoprotective properties Stoner et al., 2011;Tsuda, 2012). In recent years, scientists newly found that anthocyanins can prevent carcinogenesis, and inhibit cancer progress and metastasis through cell signal transduction (Muserref et al., 2014), including breast cancer (Chang et al., 2010;Faria et al., 2010;Adams et al., 2011), lung cancer (Ho et al., 2010), colon cancer (Ratasark et al., 2014), prostate cancer (Bilal et al., 2008;Hafeez et al., 2008) and esophageal cancer (Stoner et al., 2010). ...
... Our previous animal experiments also proved that BRACs can decrease the expressing of u-PA in tumor tissue (Chang et al., 2010). Similar results were shown in many other anthocyanins research (Xu et al., 2010;Adams et al., 2010;Ho et al., 2010). ...
... Xu's (2010) report indicated that C3G can inhibit ethanol-induced invasion by blocking the ErbB2/cSrc/FAk pathway in ErbB2 overexpressing breast cancer cells. But P3G was identified possessing metastasis inhibitory effect by downregulation of proteinases activities and MAPK pathway in lung cancer cells (Ho et al., 2010). Another research showed that dietary delphinidin inhibited NF-κB signaling pathway in human prostate PC3 cells (Hafeez et al., 2008). ...
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Background: Increasing evidence from animal, epidemiological and clinical investigations suggest that dietary anthocyanins have potential to prevent chronic diseases, including cancers. It is also noteworthy that human epidermal growth factor receptor 2 (ErbB2) protein overexpression or ErbB2 gene amplification has been included as an indicator for metastasis and higher risk of recurrence for breast cancer. Materials and methods: The present experiments investigated the anti-metastasis effects of black rice anthocyanins (BRACs) on ErbB2 positive breast cancer cells in vivo and in vitro. Results: Oral administration of BRACs (150 mg/kg/day) reduced transplanted tumor growth, inhibited pulmonary metastasis, and decreased lung tumor nodules in BALB/c nude mice bearing ErbB2 positive breast cancer cell MDA-MB-453 xenografts. The capacity for migration, adhesion, motility and invasion was also inhibited by BRACs in MDA-MB-453 cells in a concentration dependent manner, accompanied by decreased activity of a transfer promoting factor, urokinase-type plasminogen activator (u-PA). Conclusions: Together, our results indicated that BRACs possess anti-metastasis potential against ErbB2 positive human breast cancer cells in vivo and in vitro through inhibition of metastasis promoting molecules.
... Antimetastatic activity [125] HS578T breast adenocarcinoma cells 2.5-10 μmol L -1 caspase-3, CDK-1, CDK-2, cyclin B1, cyclin E Cell cycle arrest and apoptosis [137] Petunidin ...
... As expected, cyanidin glycosides inhibited the activation of NF-B and c-Jun, a part of the AP-1, both known regulators of uPA and MMP expression. Similarly, peonidin-3-glucoside could reduce the metastatic potential of lung cancer cells through inactivation of the ERK1/2 and AP-1 signaling pathways [125]. Consequently, MMP-2, MMP-9, and uPA were down-regulated, whereas overexpression of MEK1 abolished the inhibitory effects of anthocyanin. ...
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This review summarizes the current knowledge of the regulatory role of pure anthocyans in cellular signaling pathways and gene expression. The molecular basis for anthocyans pharmacological activity includes the regulation of plethora of mechanisms mainly involved in: (1) suppression of the inflammatory response through targeting the phospholipase A2 and PI3K/Akt and NF-κB pathways, (2) protection from cardiovascular disease by exerting (i) antihypertensive and endothelium-protective activity through targeting the Akt/eNOS and ACE pathways (ii) antiatherogenic activity through targeting NF-κB mediated VCAM and ICAM expression, (3) growth/differentiation control and tumor suppression by exerting (i) anticancerogenic activity through targeting the EGF and HGF signaling pathways (ii) tumor anti-invasive activity through targeting the VEGF signaling pathway and ECM degrading enzymes (iii) cell cycle arrest and induction of apoptosis through the JNK/p38 MAPK mediated caspase activation (iv) modulation of chemotherapeutic efficacy by affecting resistance to anticancer drugs, (4) reduction of diabetes incidence through modulation of insulin sensitivity and glucose utilization, (5) neuroprotection through amelioration of oxidative stress and Aβ deposition, and (6) hepatoprotective activity through interference with TNF-α and TGF-β in the liver. The estrogen-like activity of anthocyans could be utilized in cancer and hormone-replacement therapy. These data provide a concise insight into molecular mechanisms of protective and therapeutic activity of anthocyans in various pathological conditions, which may not be attributed solely to their antioxidant activity but also to direct blockage of signaling pathways. Structure-activity analysis reveals that the number of hydroxyl groups and presence of sugar moiety are crucial for their specific modulatory actions.
... Atalantraflavone, in turn, is extracted from Atalantia monophylla, and was shown to inhibit migration of NSCLC cells by increasing the degradation of Twist-related protein 1 (Twist1), a transcription factor strongly associated with EMT that promotes the expression of vimentin and N-cadherin (78). Regarding anthocyanins, cyanidin 3-rutinoside, cyanidin 3-glucoside, and peonidin 3-glucoside inhibited migration and invasion through the decrease in the secretion of u-PA, MMP-2/9, as well as inhibited the activation of AP-1, c-Jun, and NF-kB and also decreased the phosphorylation of ERK1/2 (40,79). Another study by Kausar et al. (25) showed a synergistic effect of the combination of different berry anthocyanins in the inhibition of migration and invasion of NSCLC cells as well as on apoptosis through suppression of Notch and WNT pathways. ...
... Wound-healing assay P3G inhibited invasion, motility, and secretion of MMP-2/9, and u-PA. These inhibitory effects might occur due to the inactivation of ERK 1/2 and AP-1 signalling pathways (79) Transwell migration and invasion assays ...
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Lung cancer (LC) is the leading cause of cancer deaths worldwide, being non-small lung cancer (NSCLC) sub-types the most prevalent. Since most LC cases are only detected during the last stage of the disease the high mortality rate is strongly associated with metastases. For this reason, the migratory and invasive capacity of these cancer cells as well as the mechanisms involved have long been studied to uncover novel strategies to prevent metastases and improve the patients' prognosis. This narrative review provides an overview of the main in vitro migration and invasion assays employed in NSCLC research. While several methods have been developed, experiments using conventional cell culture models prevailed, specifically the wound-healing and the transwell migration and invasion assays. Moreover, it is provided herewith a summary of the available information concerning chemical contaminants that may promote the migratory/ invasive properties of NSCLC cells in vitro, shedding some light on possible LC risk factors. Most of the reported agents with pro-migration/invasion effects derive from cigarette smoking [e.g., Benzo(a)pyrene and cadmium] and air pollution. This review further presents several studies in which different dietary/ plant-derived compounds demonstrated to impair migration/invasion processes in NSCLC cells in vitro. These chemicals that have been proposed as anti-migratory consisted mainly of natural bioactive substances, including polyphenols non-flavonoids, flavonoids, bibenzyls, terpenes, alkaloids, and steroids. Some of these compounds may eventually represent novel therapeutic strategies to be considered in the future to prevent metastasis formation in LC, which highlights the need for additional in vitro methodologies that more closely resemble the in vivo tumor microenvironment and cancer cell interactions. These studies along with adequate in vivo models should be further explored as proof of concept for the most promising compounds.
... Our present study has revealed that purple-black colored Riceberry™ rice flour comprises two major components of ACNs: C3G and P3G. Consistently, high-performance-liquid chromatographic/mass spectrometric and electron paramagnetic resonance imaging analyses have been used to identify major functional ACNs including C3G, P3G, cyanidin 3-galactoside, cyanidin 3-rutinoside, cyanidin-3,5-diglucoside, malvidin 3-galactoside and pelargonidin-3,5-diglucoside in pigmented rice, in which C3G and P3G are known to be the predominant components of the ACNs [52,55,56]. Notably, ACNs that are persistent in certain plant foods, such as pigmented rice, are unstable in the small intestines and can only be absorbed with low bioavailability. ...
... Importantly, consumption of ACNs-rich black rice extract could lower plasma TBARS and blood oxidized glutathione concentrations in high fructose diet-fed rats [79]. Furthermore, C3G and P3G, as the two main components of ACNs in black rice extract, exerted antioxidant and anti-inflammatory properties in vitro and murine macrophage RAW264.7 cells [56]. Similarly, ACNs-rich Riceberry™ bran extract was found to reduce the increase of hepatic MDA concentrations and up-regulate the expression of SOD genes in gentamycin-induced hepatotoxicity in rats. ...
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Redox-active iron generates reactive oxygen species that can cause oxidative organ dysfunction. Thus, the anti-oxidative systems in the body and certain dietary antioxidants, such as anthocyanins, are needed to control oxidative stress. We aimed to investigate the effects of dielectric barrier discharge (DBD) plasma technology in the preparation of Riceberry™ rice flour (PRBF) on iron-induced oxidative stress in mice. PRBF using plasma technology was rich in anthocyanins, mainly cyanidine-3-glucoside and peonidine-3-glucoside. PRBF (5 mg AE/mg) lowered WBC numbers in iron dextran (FeDex)-loaded mice and served as evidence of the reversal of erythrocyte superoxide dismutase activity, plasma total antioxidant capacity, and plasma and liver thiobarbituric acid-reactive substances in the loading mice. Consequently, the PRBF treatment was observed to be more effective than NAC treatment. PRBF would be a powerful supplementary and therapeutic antioxidant product that is understood to be more potent than NAC in ameliorating the effects of iron-induced oxidative stress.
... Gallic acid is distributed in plant-based fruits, and a small quantity is also found in hydrolyzable tannins. It has a variety of pharmacological activities including anticancer, antimicrobial, and anti-inflammatory activities [22]. Gallic acids are segregated from Phyllanthus emblica fruit, which has demonstrated its anti-proliferative effects against breast cancer cells. ...
... Gallic acids are segregated from Phyllanthus emblica fruit, which has demonstrated its anti-proliferative effects against breast cancer cells. In HCT-15 colon cancer cells, gallic acids (3.5 µM) showed the therapeutic potential for reducing tumour metastasis by inhibiting the activities of NF-κB and down-regulation of PI3K/AKT/small GTPase signals [22,23]. In leukaemia, gallic acid showed pro-apoptosis activity by the production of hydrogen peroxide (H 2 O 2 ) [24]. ...
Article
Natural products, especially polyphenols (phenolic acids, lignans, and stilbenes) are suggested to be more potent anticancer drugs because of their no or less adverse effects, excess availability, high accuracy, and secure mode of action. In the present review, potential anticancer mechanisms of action of some polyphenols including phenolic acids, lignans, and stilbenes are discussed based on clinical, epidemiological, in vivo, and in vitro studies. The emerging evidence revealed that phenolic acids, lignans, and stilbenes induced apoptosis in the treatment of breast (MCF-7), colon (Caco-2), lung (SKLU-1), prostate (DU-145 and LNCaP), hepatocellular (hepG-2), and cervical (A-431) cancer cells, cell cycle arrest (S/G2/M/G1-phases) in gastric (MKN-45 and MKN-74), colorectal (HCT-116), bladder (T-24 and 5637), oral (H-400), leukemic (HL-60 and MOLT-4) and colon (Caco-2) cancer cells, and inhibit cell proliferation against the prostate (PC-3), liver (LI-90), breast (T47D and MDA-MB-231), colon (HT-29 and Caco-2), cervical (HTB-35), and MIC-1 cancer cells through caspase-3, MAPK, AMPK, Akt, NF-κB, Wnt, CD95, and SIRT1 pathways. Based on accumulated data, we suggested that polyphenols could be considered as a viable therapeutic option in the treatment of cancer cells in the near future.
... It is noteworthy that dietary anthocyanin suppressed azoxymethane-induced formation of aberrant crypt foci in the colons of CF-1 mice (Lim et al., 2013). Peonidin 3-glucoside has been shown to inhibit metastasizing potential of Lewis lung carcinoma cells in cancer bearing mice (Ho et al., 2010). Prostate cancer has also been noted to be inhibited in athymic nude mice xenografted with prostate cancer cells. ...
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It is becoming progressively more understandable that phytochemicals derived from edible plants have shown potential in modelling their interactions with their target proteins. Rapidly accumulating in-vitro and in- vivo evidence indicates that anthocyanins have anticancer activity in rodent models of cancer. More intriguingly, evaluation of bilberry anthocyanins as chemopreventive agents in twenty-five colorectal cancer patients has opened new window of opportunity in translating the findings from laboratory to clinic. Confluence of information suggests that anthocyanins treated cancer cells reveal up-regulation of tumor suppressor genes. There is a successive increase in the research-work in nutrigenomics and evidence has started to shed light on intracellular-signaling cascades as common molecular targets for anthocyanins. In this review we bring to limelight how anthocyanins induced apoptosis in cancer cells via activation of extrinsic and intrinsic pathways.
... A new study suggests that two anthocyanins are known as peonidin-3-glucoside and cyaniding-3-glucoside isolated from black rice, enhance apoptosis, significantly inhibits proliferation and prevents cancer growth of a protein HER2 (human epidermal growth factor receptor 2) positive for breast cancers, whereas peonidin-3-glucoside potentially inhibited the invasion as well as metastasis of lung cancer cell lines [32,33]. The cyanidin-3-O-sambubioside could block angiogenesis of breast cancer cells [34]. A study found that cyanidin and delphinidin reveal chemopreventive activities along with cytotoxicity due to oxidative stress in colorectal cancer cells [35,36]. ...
Article
Background There is much epidemiological evidence that fruits, vegetables, medicinal plants, and their phytochemicals could lower the progression and development of various forms of cancer. The plants are active reservoirs for novel chemical entities and provide a promising resource for the management of cancer. Methods Several analyses have signified that bioactive flavonoids and phenolic acids might be widely practiced for the management as well as therapy of numerous carcinomas. A large number of research works are now focusing on natural polyphenolic compounds and trying to find out new and more effective treatment strategies for cancer patients. Results The probable mechanism comprises anti-oxidant, anti-inflammation, apoptosis and induces inhibition of cell proliferation along with genomic phenomena elaborated in cancer therapy. Conclusion In the last five years, studies investigated the antitumor potential of common polyphenolic groups (phenolic acids, flavonoids, lignins, resveratrol, stilbene, quercetin etc.) exploring the prospective mechanism, based on epidemiological data thus reporting therapeutic evidence and various clinical examinations.
... 11,12 Phenolic compounds, however, are classified into widely varying families of biomolecules, and not all families have the same effects on maintenance of health and prevention of disease. 13,14 One of the most important classes of phenolic compounds are the flavonoids, particularly the anthocyanins, which have shown promising potential in the prevention of diseases and conditions such as obesity, [15][16][17] type 2 diabetes, [17][18][19] hypertension, 20 prostate cancer, [21][22][23] lung cancer, [24][25][26] heart failure, 27 renal failure, [28][29][30] Alzheimer disease, and Parkinson disease. [31][32][33][34][35] Anthocyanins are water-soluble pigments responsible for the red or blue coloration of certain flowers, seeds, fruits, and plants. ...
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Context: Anthocyanins are phenolic compounds found in berries. They exhibit promising health benefits in humans, but no accurate biomarkers of berry intake have been identified thus far. Objective: The aim of this systematic review is to propose a biomarker of anthocyanin-rich berry intake in human plasma and urine. Data sources: PubMed and Cochrane databases were searched from January 2008 to January 2019. Study selection: Databases were searched for human intervention studies that assessed the presence of anthocyanins in human body fluids using high-throughput techniques. Non-English articles and studies publishing targeted analyses were excluded. Data extraction: Ten clinical trials, in which 203 phenolic compounds were identified, were included and assessed qualitatively. The following criteria were used to identify biomarkers of berry intake: frequency, plausibility, dose-response, time response, robustness, reliability, stability, analytical performance, and reproducibility. Sensitivity and specificity of potential biomarkers were determined by the receiver operating characteristic curve. Results: Of the 203 phenolic compounds identified in human samples, the anthocyanin cyanidin-3-glucoside was the molecule found most frequently in urine (58.06%) and plasma (69.49%). Cyanidin-3-glucoside fulfills the essential criterion of plausibility as well as the dose-response, time response, stability, and analytical performance criteria. Its positive predictive value is 74% (P = 0.210) in plasma, which is acceptable, and 61.7% (P = 0.402) in urine. Conclusions: Current evidence suggests that cyanidin-3-glucoside is a potential biomarker of anthocyanin-rich berry intake in plasma and urine of healthy humans. Prospero registration number: CRD42018096796.
... MAPK activation promotes cancer progression and resistance to chemotherapeutic drugs [30,31]. On the contrary, inhibition of MAPK pathway inhibits tumor metastasis and tumor-related angiogenesis [32,33] Ishikawa and RL95-2 cells, which was enhanced after co-transfection with sh-LINC01220 and pcDNA-MAPK11. C. LINC01220 knockdown reduced colony formation ability of Ishikawa and RL95-2 cells, which was enhanced after co-transfection with sh-LINC01220 and pcDNA-MAPK11. ...
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Background: Endometrial carcinoma (EC) still threatens the health of women. Thus, to explore how long intergenic non-protein coding RNA 01220 regulates the development of EC. Methods: Whole genome expression profile data of EC and paracancerous tissues in TCGA database were downloaded. LINC01220 expression in EC and paracancerous tissues of patients in our hospital were detected by qRT-PCR. Furthermore, the relationship between LINC01220 expression and clinicopathological features of EC patients was analyzed. After transfection with sh-LINC01220 and pcDNA-MAPK11 (mitogen-activated protein kinase) in EC cells, proliferative, colony formation abilities and apoptosis were determined by cell counting kit-8 (CCK-8), colony formation assay and flow cytometry, respectively. Western blot was conducted to determine the regulatory role of LINC01220 on MAPK11. Results: TCGA data showed that LINC01220 expression is markedly higher in EC tissues than that of paracancerous tissues, which was consistent without detection in EC patients of our hospital. LINC01220 expression was positively correlated to pathological grade and International Federation of Gynecology and Obstetrics (FIGO) stage of EC patients. After knockdown of LINC01220 in EC cells, proliferative and colony formation abilities decreased, whereas apoptotic rate increased. Cor function analysis revealed the positive correlation between LINC01220 and MAPK11 in EC. MAPK11 expression was regulated by LINC01220 in EC cells. Overexpression of MAPK11 can reverse the tumor suppressing effect of LINC01220 on EC. Conclusions: LINC01220 promotes EC development by stimulating proliferation and inhibiting apoptosis of EC cells through up-regulating MAPK11.
... Among anthocyanins, delphinidin has been shown to have strong anticancer activities, possibly due to the suppression of the NF-κB pathway [52,53]. A study found that delphinidin significantly suppressed invasion and metastasis of lung cancer cells by downregulating the matrix metalloproteinase [54]. ...
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Several epidemiological studies have investigated the association between the dietary flavonoid intake and gastric cancer (GC) risk; however, the results remain inconclusive. Investigating the relationship between the different classes of flavonoids and the histological types and origin of GC can be of interest to the research community. We used data from a population-based multi-case control study (MCC-Spain) obtained from 12 different regions of Spain. 2700 controls and 329 GC cases were included in this study. Odds ratios (ORs) were calculated using the mixed effects logistic regression considering quartiles of flavonoid intakes and log2. Flavonoid intake was associated with a lower GC risk (ORlog2 = 0.76; 95% CI = 0.65–0.89; ORq4vsq1 = 0.60; 95%CI = 0.40–0.89; ptrend = 0.007). Inverse and statistically significant associations were observed with anthocyanidins, chalcones, dihydroflavonols and flavan-3-ols. The isoflavanoid intake was positively associated with higher cancer risk, but without reaching a statistical significance. In general, no differences were observed in the GC risk according to the location and histological type. The flavonoid intake seems to be a protective factor against GC within the MCC-study. This effect may vary depending on the flavonoid class but not by the histological type and location of the tumor. Broader studies with larger sample size and greater geographical variability are necessary.
... Lyophilized black raspberries (LBRs) inhibited AOM-induced colon carcinogenesis in rats, when fed rats at 2.5%, 5.0% and 10% LBRs of the diet, the incidence of tumor did not be reduced, but the total tumor (adenoma & adenocarcinoma) multiplicity was reduced by 42%, 45% and 71% (P < 0.05) relative to AOM controls respectively (Harris et al. 2001). In vitro and in vivo, berries and its phytochemicals have great therapeutic activity against lung cancer (Ho et al. 2010), breast cancer and prostate cancer (Adams et al. 2010;Hafeez et al. 2008;Nguyen et al. 2010). ...
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Cardiovascular disease (CVD), cancer and diabetes are serious threat to human health and more and more aroused people's attention. It is important to find the safe and effective prevention and treatment methods for the three deadly diseases. At present, a generally attention in the possible positive effects of edible berries for the three deadly diseases has been noted. Berry phytochemical compounds regulate different signaling pathways about cell survival, growth and differentiation. They contribute to the prevention and treatment of CVD, cancer and diabetes. This article reviews previous experimental evidence, several common berry phytochemical compounds and their possible mechanisms involved in three deadly diseases were summarized.
... 76 These anticancer benefits might be specifically provided by P3G, an ACN which has demonstrated to inhibit the invasion, motility, and secretion of MMPs such as MMP-2, MMP-9, and urokinasetype plasminogen activator in lung cancer cells, by inhibiting extracellular signal-regulated kinase (ERK)-1/2, a mitogenactivated protein kinase (MAPK) family member involved in the regulation of MMP molecules as demonstrated in a lung cancer cell in vitro model. 77 Furthermore, so-called suboptimal in vitro concentrations of a combination of ACNs have demonstrated to act synergistically inhibiting the growth of aggressive non-small-cell lung cancer cells, possibly by their inhibitory effects on molecules like β-catenin, cyclin B1, and MMP-9 as well as the inhibition of TNFα-induced nuclear factor-kappa B (NF-κB) activation. 78 Delphinidin is another ACN that has shown anticancer properties. ...
Article
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Anthocyanins (ACNs) are promising health-enhancing phenolic compounds. We focus on ACNs animal tissue bioavailability to provide an evidentiary link between tissue ACNs and their associated health properties. We performed a systematic review of electronic libraries. 279 results were retrieved, 13 publications met inclusion criteria. Extracted information included animal model employed, administration route, doses, analysis method, and ACN concentration values in tissues. Total ACNs concentrations were detected in mice kidney (2.17x10⁵ pmol/g), liver (1.73x10⁵ pmol/g), heart (3.6x10³ pmol/g), lung (1.16x10⁵ pmol/g); and pig brain (6.08x10³ pmol/g). ACNs showed a predominance of parent ACNs in long-term experiments versus an ACN metabolite predominance in short-term experiments. ACNs detected in animal tissues, such as cyanidin-3-glucoside (C3G), suggesting it may have an important role in human health. This information could be useful to determine proper ACN-intake biomarkers in biological samples in futures studies.
... Among the compounds characterized in COME, flavonoids have been largely studied for their anti-inflammatory and anti-tumor activity, and specific members of this family detected in the same extract, namely chrysin, quercetin-O-glucoside, and diosmetin, have been reported as NF-κB and AP-1 blockers [54][55][56][57][58]. Also phenolic acids have been already studied for their anti-inflammatory activity, and compounds such as chlorogenic acids, ferulic acid and quinic acid, characterized in COME, have been reported to attenuate the production of pro-inflammatory cytokines in murine cells by down regulating the NF-κB pathway [59][60][61]. Among the other compounds identified in COME, the two coumarins umbelliferone and methoxsalen have been reported to suppress the expression of NF-κB in animal models [62,63], while peonidin-3-glucoside to reduce the metastasis of lung cancer cells by acting via different mechanisms, among which the blocking of AP-1 activation [64]. Overall, these constituents could also contribute to the observed anti-inflammatory and cytotoxic activities of COME. ...
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Here we report the comprehensive characterization of the secondary metabolites from the leaves of Colebrookea oppositifolia Smith, a species used as medicinal plant in the traditional medicine of Nepal. Phytochemical screening of bioactives was performed using an integrated LC-MSn and high resolution MS (Mass Spectrometry) approach. Forty-three compounds were tentatively identified, mainly aglyconic and glycosilated flavonoids and phenolic acids, as well as other bioactives such as coumarins and terpenes were detected. Furthermore, the NF-κB and AP-1 inhibitory activity of C. oppositifolia extract were evaluated, as well as its cytotoxicity against THP-1 cells, in order to assess the potential use of this herb as a source of anti-inflammatory and cytotoxic compounds. The results so far obtained indicate that C. oppositifolia leaves extract could significantly reduce the viability of THP-1 cells (IC50 = 6.2 ± 1.2 µg/mL), as well as the activation of both NF-κB and AP-1 at the concentration of 2 μg/mL. Our results indicate that Nepalese C. oppositifolia is a valuable source of anti-inflammatory and cytotoxic compounds. The phytochemical composition reported here can partially justify the traditional uses of C. oppositifolia in Nepal, especially in the treatment of inflammatory diseases, although further research will be needed to assess the full potential of this species.
... Among the six typical anthocyanins, peonidin-3glucoside is reported to downregulate ERK 1/2 expression in the H1299 cell line [155]. Anthocyanin-rich pomegranate extract also had a positive effect on UV-B-mediated phosphorylation of MAPKs pathway in normal human epidermal keratinocytes. ...
Article
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Anthocyanins are colored water-soluble pigments belonging to the phenolic group. The pigments are in glycosylated forms. Anthocyanins responsible for the colors, red, purple, and blue, are in fruits and vegetables. Berries, currants, grapes, and some tropical fruits have high anthocyanins content. Red to purplish blue-colored leafy vegetables, grains, roots, and tubers are the edible vegetables that contain a high level of anthocyanins. Among the anthocyanin pigments, cyanidin-3-glucoside is the major anthocyanin found in most of the plants. The colored anthocyanin pigments have been traditionally used as a natural food colorant. The color and stability of these pigments are influenced by pH, light, temperature, and structure. In acidic condition, anthocyanins appear as red but turn blue when the pH increases. Chromatography has been largely applied in extraction, separation, and quantification of anthocyanins. Besides the use of anthocyanidins and anthocyanins as natural dyes, these colored pigments are potential pharmaceutical ingredients that give various beneficial health effects. Scientific studies, such as cell culture studies, animal models, and human clinical trials, show that anthocyanidins and anthocyanins possess antioxidative and antimicrobial activities, improve visual and neurological health, and protect against various non-communicable diseases. These studies confer the health effects of anthocyanidins and anthocyanins, which are due to their potent antioxidant properties. Different mechanisms and pathways are involved in the protective effects, including free-radical scavenging pathway, cyclooxygenase pathway, mitogen-activated protein kinase pathway, and inflammatory cytokines signaling. Therefore, this review focuses on the role of anthocyanidins and anthocyanins as natural food colorants and their nutraceutical properties for health. Abbreviations: CVD: Cardiovascular disease VEGF: Vascular endothelial growth factor
... Probably the high P3G-mal could be playing a larger part in effectively inhibiting the growth of the cancer cells. Ho et al. (2010) discovered that P3G had a slight inhibitory effect on lung cancer cell viability and significant reduction in cell migration and in proteins promoting invasion indicating its potential anti-metastatic capabilities. The percentages of inhibition at 10 mg/mL of PW for HT-29, HCT-116, and CCD-33Co cells were 93.0%, 86.8%, and 23.4%, respectively; the percentages of inhibition at the same concentration of PAWE for HT-29, HCT-116, and CCD-33Co cells were 88.2%, 88.2%, and 31.9%, ...
Article
Anthocyanin-rich foods have shown potential health benefits. The objective was to evaluate the anti-proliferative effect of anthocyanin-rich purple and red corn on HCT-116 and HT-29 human colorectal cancer cells. IC50 values ranged from 1.1 to 6.3 mg/mL, suggesting the corn extracts exhibited anti-proliferative effects on colon cancer cells; the red corn had the highest potential. All extracts increased apoptotic cells and impacted markers of apoptosis (BAX, Bcl-2, cytochrome c, TRAILR2/D5). Angiogenesis markers were also affected; a decreased expression of VEGF resulted with all corn extracts. Red corn significantly reduced other important markers of angiogenesis like Tie-2. Free binding energy of anthocyanins to tyrosine kinases was estimated at −7.86 and −7.76 kcal/mol for cyanidin-3-glucoside with a non-receptor tyrosine kinase and peonidin with a receptor tyrosine kinase, respectively. The results indicate that anthocyanin-rich purple and red corn can potentially inhibit human colon cancer cell proliferation through promoting apoptosis and suppressing angiogenesis.
... Anthocyanins display a wide range of biological effects, including antioxidant, anti-inflammatory, anti-proliferative cell, anti-angiogenic, and anti-invasive activities, as well as inducing apoptosis and presenting chemo-protective effect [67] ( Table 1). Anthocyanins inhibit cancer progress and metastasis through cancer cell signaling [68], in lung cancer [69], colon cancer [70], prostate cancer [71] and esophageal cancer [72]. Anthocyanins from purple fleshed sweet potato P40 cultivar are reported to block the cell cycle at the G1 phase in human colon SW480 cancer cells [73]. ...
Article
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Anthocyanins, a flavonoid class of polyphenols, are water soluble dark colored natural pigments found in fruits and vegetables. Owing to their wide distribution in plant materials, dietary consumption of anthocyanins is high compared to other flavonoids. Anthocyanins, due to their multifaceted medicinal properties are the active components in many herbal folk medicines. As in vitro and in vivo results, animal models, and clinical trials in various cell lines suggest, anthocyanins possess antioxidant, antidiabetic, antihyperlipidemic, anti-inflammatory, anticarcinogenic, antiulcer, and preventive activities against cardiovascular diseases. Additionally, anthocyanins exhibit chemotherapeutic, cardioprotective, hepatoprotective, and neuroprotective activities. In the diet, anthocyanins are absorbed in the stomach and intestinal cells and rapidly detected in the plasma. These promising properties of anthocyanins may well provide health benefits against chronic diseases.
... A study found that two anthocyanins extracted from black rice, peonidin-3-glucoside and cyaniding-3-glucoside, could induce apoptosis and selectively decrease cell proliferation and tumor growth of HER2 positive breast cancer [32]. In addition, peonidin-3-glucoside treatment significantly suppressed invasion and metastasis of lung cancer cells by down-regulating the matrix metalloproteinase (MMP) [33]. In similar ways, cyanidin-3-O-sambubioside from Acanthopanax sessiliflorus fruit inhibited angiogenesis and invasion of breast cancer cells [34]. ...
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There is much epidemiological evidence that a diet rich in fruits and vegetables could lower the risk of certain cancers. The effect has been attributed, in part, to natural polyphenols. Besides, numerous studies have demonstrated that natural polyphenols could be used for the prevention and treatment of cancer. Potential mechanisms included antioxidant, anti-inflammation as well as the modulation of multiple molecular events involved in carcinogenesis. The current review summarized the anticancer efficacy of major polyphenol classes (flavonoids, phenolic acids, lignans and stilbenes) and discussed the potential mechanisms of action, which were based on epidemiological, in vitro, in vivo and clinical studies within the past five years.
... Our data, however, support that ACN and/or their metabolites occurring in plasma in low physiological concentrations inhibited migration of PANC-1 cells. Nevertheless, it remains to be shown whether reduced mRNA levels of MMP-2, MMP-9, and NF-κB correspond with protein expression and/or activity as shown by Ho et al. and Cheng et al. [83][84][85]. However, referring to mRNA levels of target genes only is a limitation of our study and should be extended to measurements of protein expression and activity in future studies. ...
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Purpose: Pancreatic cancer is an aggressive cancer type, of which the most important characteristics are migration and metastasis. Anthocyanins (ACN) are discussed to be protective phytochemicals; however, up to now only scarce data are available regarding their effects on cancer prevention. In this study, we aimed to determine whether ACN and their metabolites from plasma (PAM), isolated from blood of healthy volunteers after ingestion of an ACN-rich juice, are effective in modulating cancer cell migration in vitro. Methods: PAM were isolated from blood of healthy volunteers (n = 10) after consumption of an ACN-rich berry juice. Before ingestion (PAM0min) and after 60 min (PAM60min), blood was taken and PAM were isolated from plasma by solid-phase extraction. Migration of pancreatic cancer cells PANC-1 and AsPC-1 was assayed in a Boyden chamber. The influence of PAM on cellular reactive oxygen species (ROS) or mitochondria-specific ROS was measured fluorimetrically. mRNA expression levels of matrix metalloproteinases (MMP-2 and MMP-9) and NF-κB mRNA were determined by real-time PCR. Results: After application of PAM60min to PANC-1, we observed a reduced cell migration, which was associated with reduced levels of endogenously generated ROS concomitant with reduced NF-κB as well as MMP-2 and MMP-9 mRNA expression levels. In AsPC-1 cells, however, migration was not affected by PAM60min. Conclusion: It can be assumed that physiologically relevant ACN and their metabolites were able to inhibit pancreatic cancer cell migration in dependency of the phenotype of cells and may thus deserve further attention as potential bioactive phytochemicals in cancer prevention.
... Here, we show that peach flowers accumulate a variety of anthocyanins, whereas the fruits and leaves predominantly accumulate a single anthocyanin, Cy-3-glu. Several studies have demonstrated that both peonidin-based and cyanidin-based anthocyanins can inhibit cancer cell growth (Chen et al., 2005;Ho et al., 2010). Therefore, peach flowers are a more suitable ingredient to use in medicine than leaves and fruits in terms of the anthocyanin benefits. ...
Article
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Modification of anthocyanin plays an important role in increasing its stability in plants. Here, six anthocyanins were identified in peach (Prunus persica) and their structural diversity is attributed to glycosylation and methylation. Interestingly, peach is quite similar to the wild species P. ferganensis, but differs from both P. davidiana and P. kansueasis in terms of anthocyanin composition in flowers. This indicates that peach is probably domesticated from P. ferganensis. Subsequently, genes responsible for both methylation and glycosylation of anthocyanins were identified, and their spatiotemporal expression results in different patterns of anthocyanin accumulation in flowers, leaves, and fruits. Two tandem-duplicated genes encoding flavonoid 3-O-glycosyltransferase (F3GT) in peach, PpUGT78A1 and PpUGT78A2, showed different activity towards anthocyanin, providing an example of divergence evolution of F3GT genes in plants. Two genes encoding anthocyanin O-methyltransferase (AOMT), PpAOMT1 and PpAOMT2, are expressed in leaves and flowers, but only PpAOMT2 is responsible for the O-methylation of anthocyanins at 3' position in peach. In addition, our study reveals a novel branch of UGT78 genes in plants, which are lack of the highly conserved intron 2 of the UGT gene family, with a great variation of the amino acid residue at position 22 of plant secondary product glycosyltransferase (PSPG) box. Our results not only provide insights into mechanisms underlying anthocyanin glycosylation and methylation in peach, but will also aid in future attempts to manipulate flavonoid biosynthesis in peach as well as in other plants.
... Natural polyphenols have anticancer effects mainly due to their powerful antioxidant and anti-inflammatory actions, additionally their effectiveness to modulate molecular targets and signaling pathways, which were affiliated with cell life, migration, separation, proliferation, immune responses, detoxification enzymes, angiogenesis, hormone activities, etc. [30][31][32][33][34][35] .Including, anthocyanins, delphinidin has strong anticancer activities; it Journal of Pure and Applied Microbiology follows the mechanism of induced apoptosis and cell cycle arrest in different classes of cancer. Peonidin-3-glucoside and cyanidin-3glucoside induce apoptosis and selectively reduced cell proliferation and abnormal development with HER2 positive breast cancer, and also repressed lung cancer cells growth by down-regulating the matrix metalloproteinase (MMP) expression [36][37][38][39] . Cyanidin-3-O-sambubioside has a preventive effect and also suppresses the development of breast cancer cells 40 . ...
Article
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In this article, an attempt has been made review on phenolics antioxidant activity, and characteristics, as well as the constituents of the different phenolics present in various consumable food items, which reduce the risk of non-communicable diseases. Some polyphenolic compounds are present in selected species, which are beneficial to public health, and it should be comprised as component of food habits for a proper nutrition’s plan. Polyphenols are basically a natural compound and their micronutrients are found in different fruits, beverages, and vegetables. There is no specific deficiency disease caused due to the low dietary intake of phenolics; while the proper intake possibly gives health benefits. Polyphenols are antioxidants, and evidence for their role with improved heart health, neurodegenerative (Alzheimer’s disease) diseases, better blood sugar control, diabetes, reduced inflammation, and a reduced risk of cancer development was studied. A comprehensive understanding of the biological availability of the nutritional polyphenols will helpful to recognize those that are beneficial and protective for human health. Based on latest reports, polyphenolic compounds occupy a unique place in environmental science as an important and common class of bioactive natural products globally. It is building a bridge between different interdisciplinary academic fields of science. This work is based on the reports examined the health effect of polyphenols until today.
... A new study suggests that two anthocyanins are known as peonidin-3-glucoside and cyaniding-3-glucoside isolated from black rice, enhance apoptosis, significantly inhibits proliferation and prevents cancer growth of a protein HER2 (human epidermal growth factor receptor 2) positive for breast cancers, whereas peonidin-3-glucoside potentially inhibited the invasion as well as metastasis of lung cancer cell lines [32,33]. The cyanidin-3-O-sambubioside could block angiogenesis of breast cancer cells [34]. A study found that cyanidin and delphinidin reveal chemopreventive activities along with cytotoxicity due to oxidative stress in colorectal cancer cells [35,36]. ...
Article
Background: There is much epidemiological evidence that fruits, vegetables, medicinal plants, and their phytochemicals could lower the progression and development of various forms of cancer. The plants are active reservoirs for novel chemical entities and provide a promising resource for the management of cancer. Methods: Several analyses have signified that bioactive flavonoids and phenolic acids might be widely practiced for the management as well as therapy of numerous carcinomas. A large number of research works are now focusing on natural polyphenolic compounds and trying to find out new and more effective treatment strategies for cancer patients. Results: The probable mechanism comprises anti-oxidant, anti-inflammation, apoptosis and induces inhibition of cell proliferation along with genomic phenomena elaborated in cancer therapy. Conclusion: In the last five years, studies investigated the antitumor potential of common polyphenolic groups (phenolic acids, flavonoids, lignins, resveratrol, stilbene, quercetin etc.) exploring the prospective mechanism, based on epidemiological data thus reporting therapeutic evidence and various clinical examinations.
... *p < 0.05 and **p < 0.01 versus control 1 3 [33,34]. The p-p65 protein is usually taken as a measure of nuclear translocation of NF-κB transcription factors, and c-Jun and c-Fos protein are famous AP-1 transcription factors [35]. Their expressions were investigated in nuclear extract of DU145 and PC-3 cells. ...
Article
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Chelerythrine is a natural benzo[c]phenanthridine alkaloid found in many herbs and displays a wide range of antitumor activities. Here, the present study tested their effects on prostate cancer cells. The addition of chelerythrine can significantly inhibit the proliferation of androgen-independent prostate cancer DU145 and PC-3 cells at the concentration of 5 and 10 μM, but not on androgen-dependent prostate cancer LNCaP cells as well as normal prostate epithelial cell line PrEC cells. Wound migration and transwell invasion assay showed the similar inhibitory effect of chelerythrine on the migration and invasion of DU145 and PC-3 cells in the same condition. Western blot analysis further confirmed that chelerythrine not only dramatically decreased MMP-2, MMP-9, and uPA protein expression, but also augmented the expression of their endogenous inhibitors (TIMP-1 and TIMP-2) and plasminogen activator inhibitors (PAI-1 and PAI-2) in both cancer cells. Meanwhile, NF-κB and AP-1 transcription factors were all suppressed as evidenced by the decline of p-p65, c-Fos, and c-Jun protein expression in both cells. Taken together, these findings suggested that chelerythrine could reduce the metastasis of androgen-independent prostate cancer cells via modulation of MMP/TIMP system and inactivation of NF-κB pathway.
... Yan et al. found that cyanidin-3-galactoside isolated from cranberry fruit extract was capable of scavenging free radicals and inhibiting the oxidation of low-density lipoproteins [20]. Ho et al. performed studies in mice and found that peonidin-3-glucoside reduced the number of the metastases of lung carcinoma cells [21]. Smeriglio et al. found a glycemia-lowering effect of cyanidin-3-glucoside [22]. ...
Article
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In this study, we conducted an analysis of the qualitative and quantitative composition of anthocyanins and anthocyanidins in different cultivars and genetic clones of American cranberries grown in Lithuanian climatic conditions. Four anthocyanin compounds predominated in fruit samples of American cranberry cultivars: cyanidin-3-galactoside, cyanidin-3-arabinoside, peonidin-3-galactoside, and peonidin-3-arabinoside. They accounted for 91.66% ± 2.79% of the total amount of the identified anthocyanins. The total anthocyanin content detected via the pH differential method was found to be by about 1.6 times lower than that detected via the UPLC method. Hierarchical cluster analysis and principal component analysis showed that the ‘Woolman’ cultivar distinguished from other cranberry cultivars in that its samples contained two times the average total amount of anthocyanins (8.13 ± 0.09 mg/g). The group of American cranberry cultivars ‘Howes’, ‘Le Munyon’, and ‘BL-8’ was found to have higher than average levels of anthocyanidin galactosides (means 3.536 ± 0.05 mg/g), anthocyanidins (means 0.319 ± 0.01 mg/g), and total anthocyanins (means 6.549 ± 0.09 mg/g). The evaluation of the antioxidant effect of cranberry fruit sample extracts showed that the greatest radical scavenging activity of the cranberry fruit extracts was determined in the fruit samples of ‘Woolman’ (849.75 ± 10.88 µmol TE/g) and the greatest reducing activity was determined in ‘Le Munyon’ (528.05 ± 12.16 µmol TE/g). The study showed a correlation between the total anthocyanin content and the antiradical and reductive activity of the extracts in vitro (respectively, R = 0.635 and R = 0.507, p < 0.05).
... In the present study the applied anthocyanin-rich juice was made from an eighty/twenty mixture of red grapes and bilberries with peonidin-3,5-O-diglucoside, malvidin-3,5-O-diglucoside, and peonidin-3-O-glucoside representing the major anthocyanins. It has been shown that peonidin-3-O-glucoside significantly inhibits MMP secretion and migration of lung cancer cells [58]. In addition, peonidin has been reported to be the most potent anthocyanidin comparing the anti-migratory and anti-invasive capabilities of the five anthocyanidins cyanidin, malvidin, peonidin, petunidin, and delphinidin [59]. ...
Article
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Cancer mortality is mainly due to metastasis. Therefore, searching for new therapeutic agents suppressing cancer cell migration is crucial. Data from human studies regarding effects of anthocyanins on cancer progression, however, are scarce and it is unclear whether physiological concentrations of anthocyanins and their metabolites reduce cancer cell migration in vivo. In addition, interactions with chemotherapeutics like 5-fluorouracil (5-FU) are largely unknown. Thus, we combined a placebo-controlled, double-blinded, cross-over study with in vitro migration studies of colon cancer cell lines to examine the anti-migratory effects of plasma-isolated anthocyanins and their metabolites (PAM). Healthy volunteers (n = 35) daily consumed 0.33 L of an anthocyanin-rich grape/bilberry juice and an anthocyanin-depleted placebo juice for 28 days. PAM were isolated before and after intervention by solid-phase extraction. HT-29 and Caco-2 cells were incubated with PAM in a Boyden chamber. Migration of HT-29 cells was significantly inhibited by PAM from juice but not from placebo. In contrast, Caco-2 migration was not affected. Co-incubation with 5-FU and pooled PAM from volunteers (n = 10), which most effectively inhibited HT-29 migration, further reduced HT-29 migration in comparison to 5-FU alone. Therefore, PAM at physiological concentrations impairs colon cancer cell migration and may support the effectiveness of chemotherapeutics.
... This pathway has also been shown to play a key role in tumor progression [72]. Other researchers suggest that peonidin 3-O-glucoside may inhibit the metastasis of lung cancer cells via a mechanism of impairment of the phosphorylation of extracellular signalregulated kinase (ERK)1/2, a member of the family of mitogen-activated protein kinases (MAPK) and also inhibits the activator protein-1 (AP-1) [73]. Interesting reports on the activity of pomegranate extract, a rich source of anthocyanin compounds, include the find-ings of American researchers who showed a positive effect of the extract at a concentration of 20 µg/mL on the UV-B-dependent phosphorylation of the MAPK pathway (ERK l/2, protein p38, and JNK 1/2) in human epithelial keratinocytes [74]. ...
Article
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Inflammation plays an important role in the pathogenesis of many diseases, including cardiovascular diseases, atherosclerosis, diabetes, asthma, and cancer. An appropriate diet and the active compounds contained in it can affect various stages of the inflammatory process and significantly affect the course of inflammatory diseases. Recent reports indicate that polyphenolic acids, vitamins, minerals, and other components of fruits may exhibit activity stimulating an anti-inflammatory response, which may be of importance in maintaining health and reducing the risk of disease. The article presents the latest data on the chemical composition of fruits and the health benefits arising from their anti-inflammatory and antioxidant effects. The chemical composition of fruits determines their anti-inflammatory and antioxidant properties, but the mechanisms of action are not fully understood.
... Studies have suggested that peonidin 3-glucoside (P3G), as a kind of flavonoids, can inhibit lung cancer cells in a variety of ways, such as lowering the extracellular signal-regulated kinase (ERK) pathway to inhibit H2199 cell invasion, inhibiting the mitogen-activated protein kinase (MAPK) pathway and regulating extracellular matrix (ECM) degradation protease to inhibit the invasion and activity of lung cancer cells. Moreover, experiments have confirmed that P3G has no toxic effect [21]. Eicosanoid which produced by arachidonic acid (AA) with lysyl oxidase (LOX) metabolism is related to cancer. ...
Article
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Cancer is the second leading cause of death globally. Millions of persons die due to cancer each year. In the last two decades, the anticancer effects of natural flavonoids have become a hot topic in many laboratories. Meanwhile, flavonoids, of which over 8000 molecules are known to date, are potential candidates for the discovery of anticancer drugs. The current review summarizes the major flavonoid classes of anticancer efficacy and discusses the potential anti-cancer mechanisms through inflammation and oxidative stress action, which were based on database and clinical studies within the past years. The results showed that flavonoids could regulate the inflammatory response and oxidative stress of tumor through some anti-inflammatory mechanisms such as NF-κB, so as to realize the anti-tumor effect.
... 75 Ho et al. showed that peonidin-3-glucoside downregulated ERK 1/2 expression in the H1299 cell line. 84 Afaq and colleagues demonstrated that anthocyanin-rich PE extended a positive inhibitory effect on UVB-mediated phosphorylation of MAPKs pathway in normal human epidermal keratinocytes. 85 Shin et al. showed Vitis coignetiae Pulliat extract to extend anti-cancer function. ...
... Peonidin is naturally existed as peonidin 3-glucoside (P3G), its glycosylated form. A study shows that P3G can significantly suppress lung cancer metastasis by attenuating ERK 1/2 and AP-1 and activating the MAPK pathway (100). P3G inhibits the proliferation and tumor growth of lung cancer cells by arresting the G2/M phase via the downregulation of cell cycle-related proteins such as CDK-1, CDK-2, and cyclin B1 (101). ...
Article
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Background: Wine is one of the oldest and most popular drinks worldwide, which is rich in phenolic compounds. Epidemiological studies show that moderate consumption of wine can reduce the risk of certain diseases, and this effect is attributed to its phenolic compounds. Objective: The objective of this review was to elaborate the effects of wine-derived phenolic compounds for preclinical anticancer therapeutics and their major mechanisms. Methods: In this review, we discuss the classification and content of common phenolic compounds in wine and summarize previous studies that have evaluated the anticancer properties of wine-derived phenolic compounds and their mechanisms. Results: Wine-derived phenolic compounds have been proven to participate in several mechanisms against cancers, including deoxyribonucleic acid damage, oxidative stress, cell proliferation, cell cycle arrest, cell apoptosis, autophagy, cell invasion and metastasis, immunity and metabolism, regulation of multiple signaling molecules, and gene expression. However, the exact anticancer mechanisms of the phenolic compounds in wine need to be further investigated. Conclusion: Wine-derived phenolic compounds are promising chemoprotective and chemotherapeutic agents for cancer.
... (anticancer and antiatherogenic properties [111], prevention of osteoporosis [112], cardioprotective activity [113], Antimutagenic activity [114], antiinflammatory activity [115], hepatoprotective activity [116], antifibrotic activity [117], antimicrobial activity [118], antidiabetic activity [119], hypolipidemic activity [120], antidepressant activity [121]); Eriodictoyl (for the treatment of cancer [122], antiinflammatory properties [123], antioxidant activity [124], cardioprotective properties [125], immunomudulatory effect [126], neurotrophic, and anti-melanogenesis and anti-genotoxic properties [127]); Hesperetin (antioxidant activity [128], cardioprotective activity [129], vasodilatory effect [130], neuroprotective effect [131], antiallergic activity [132], dermatitis inhibiting effect [133], antibacterial activity [134]); Sakuranetin (anticancer properties [135], antiviral effect [136 ], anti-mutagenic properties [137], anti-diabetic activity [138], antimicrobial activity [139] Anthocyanidin present in fruits is cyanidin-3 glucoside, Grapes, blueberry, red onions, oranges, and red wine. Blackcurrant, blackberry, and elderberry (only cyanide), present in epidermal tissues of fruits and flower Cyanidin (anticarcinogenic activity [140], vasoprotective nature [141], antiinflammatory properties [142], anti-obesity [143], antidiabetic activity [144]); Delphinidin (antimutagenic activity [145], anti-cancer [146], antiangiogenic activity [147], antiinflammatory activity [148], antifibrotic activity [149], antioxidant [150]); Malvidin (anticancer activity [151 ], anti-obesity [152], antioxidant and anti-inflammatory activity [153]); Pelargonidin (antiinflammatory activity [154], antiseptic effect [155], anti-tumour activity [156], antiobesity activity [157], antithrombotic and antiplatelet activity [158], antiseptic properties [159], anti-diabetic activity [160]); Peonidin (antioxidant and prebiotic activity [161], antiinflammatory activity [162], antitumour activity [163], Antimutagenic activity [164] Soybeans and soy products are almost the sole dietary source of isoflavones. It is also in small amounts in chickpeas. ...
Chapter
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Phenolic compounds play an essential role in plants and foods. These compounds are well known for their biological and pharmaceutical activities. These compounds act as colorants and antioxidants. Research on phenolic compounds is mainly focused on their antioxidant properties. These compounds showed significant effects on chronic degenerative diseases, such as central neurodegenerative disorders, cataracts, macular degeneration (age-related), diabetes mellitus, cardiovascular complication, and cancer. These compounds also showed implications on human health since increased exposure to free radicals might lead to an increased risk of degenerative diseases. Fruits and vegetables are rich in phenolic compounds. The phenolic compound consists of one (phenolic acids) or more polyphenols aromatic structures attached to a hydroxyl group. The phenolic compound is found in combination with mono or polysaccharides, and they can occur in the group as an ester or methyl ester. Their biological and pharmaceutical activities are based on their phenolic ring and a hydroxyl group. Apart from antioxidant activity, they have many other therapeutic effects on human health. Among the several classes of phenolic compounds, flavonoids, tannins, and phenolic acids are considered as main dietary phenolic compounds. In this chapter, we have summarized the biological and pharmaceutical activities related to different classes of phenolic compounds.
Article
Metastasis is the most common cause of cancer-related death in patients, and epithelial to mesenchymal transition (EMT) is essential for cancer metastasis, which is a multistep complicated process that includes local invasion, intravasation, extravasation, and proliferation at distant sites. When cancer cells metastasize, angiogenesis is also required for metastatic dissemination, given that an increase in vascular density will allow easier access of tumor cells to circulation and represents a rational target for therapeutic intervention. Berberine has several anti-inflammation and anticancer biological effects. In this study, we provided molecular evidence that is associated with the anti-metastatic effect of berberine by showing a nearly complete inhibition on invasion (P < 0.001) of highly metastatic SiHa cells via reduced transcriptionally activities of matrix metalloproteinase-2 and urokinasetype plasminogen activator. Berberine reversed transforming growth factor-β1-induced EMT and caused upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and snail-1. Selective snail-1 inhibition by snail-1-specific-siRNA also showed increased E-cadherin expression in SiHa cells. Berberine also declined tumor-induced angiogenesis in vitro and in vivo. Importantly, in vivo BALB/c nude mice xenograft model and tail vein injection model showed that berberine treatment reduced tumor growth and lung metastasis by oral gavage, respectively. Taken together, these findings suggested that berberine could reduce metastasis and angiogenesis of cervical cancer cells, thereby constituting an adjuvant treatment for metastasis control.
Chapter
Anthocyanins are natural polyphenolic compounds widely distributed as pigments in many fruits and vegetables. In addition to displaying antioxidant properties, these nutraceuticals exhibit anti-inflammatory, anti-proliferative, and pro-apoptotic activities suggesting their potential as novel chemotherapeutic agents. Through cell cycle down-regulation, and context-specific pro-oxidant activity, anthocyanins induce cytotoxicity in cancer cells in vitro and in vivo. Specifically, via regulation of the Bcl-2 protein family and induction of caspase-dependent or caspase-independent apoptotic pathways, anthocyanins inhibit the growth of cancers by inducing cell death. Moreover, by modulating the activities of specific kinases and proteases, including (but not limited to) cyclin-dependent kinases, mitogen-activated protein kinases, matrix metalloproteases, and urokinase-type plasminogen activators, anthocyanins induce apoptosis, inhibit motility, and suppress invasion of cancer cells. In marked contrast to their effects in cancer cells, we have found that anthocyanins display significant anti-apoptotic activity in neurons. Antioxidant properties of these nutraceuticals, particularly at the level of the mitochondria, appear to underlie their neuroprotective effects. The opposing effects of anthocyanins on cancer cells and neurons suggest that these nutraceuticals are promising candidates for development as either chemotherapeutic agents or novel neuroprotective compounds for the treatment of cancers or neurodegenerative diseases, respectively. © 2012 Springer Science+Business Media Dordrecht. All rights are reserved.
Chapter
Since time immemorable, spices have been known to combat the onslaught of various microbes like bacteria, fungi and viruses, responsible for various diseases. These microbes also led to food spoilage, which in turn reduced its shelf life. Spices can be used as food preservatives instead of chemical preservatives that are harmful to our health. Studies have proven that the spices commonly used in the kitchen like pepper, clove, ginger, coriander, garlic, cinnamon, etc., are highly potent anti-microbial agents. Moreover, they are also eminent anti-inflammatory and carminative agents. The essential oils in spices are also used for protection against various pathogens in plants. These properties are due to the various chemical compounds like eugenol, gingerol, flavonoids, terpenes, anthocyanins, phenylpropanoids and various organosulphur compounds among others present in spices. Hence, spices can be exploited for food preservation and in the pharmaceutical industries. They can also be used as biopesticides, insecticidal agents, antioxidants and natural colorants. This chapter highlights the effect of various spices on various micro-organisms, the various metabolites in spices that lend this ability, and also reviews the various works undertaken to understand the antimicrobial activity of spices.
Article
Epithelial-to-mesenchymal transition (EMT) and invasion potential have been considered as essential factors in cancer metastasis, which is the major cause of cancer death. EMT is a multi-step process that involves gain invasion, cytoskeleton change, cell adhesion, and proteolytic extracellular matrix degradation. Epicatechin-3-gallate (ECG), which is a natural polyphenolic component of green tea, elicits several antioxidant and anti-inflammatory effects. However, the effects of ECG on cancer invasion and EMT of human lung carcinoma remain unknown. We provided molecular evidence supporting the anti-metastatic effect of ECG. This compound suppressed the invasion (P < 0.001) of highly metastatic A549 cells by reducing the activities of matrix metalloproteinase-2 (P < 0.001) and urokinasetype plasminogen activator (P < 0.001). ECG also reversed the transforming growth factor (TGF)-β1-induced EMT and upregulated epithelial markers, such as E-cadherin. Conversely, ECG inhibited mesenchymal markers, such as fibronectin and p-FAK. The subcutaneous inoculation of this compound also inhibited the tumor growth of the A549 cells in vivo. Therefore, ECG may be used as an anti-cancer and anti-invasion agent for the adjuvant treatment and metastasis control of human lung cancer cells. ECG may also be administered as an effective chemopreventive agent against TGF-β1-induced EMT.
Chapter
Spices have been used since ancient times as a flavoring agent as well as an important medicinal resource. Biotechnology, using strategies such as cell, organ, and tissue culture, genetic engineering, and the application of nucleic acid markers can escalate the productivity and efficiency of spices. Cell, tissue, and plant organ culture have enabled the rapid and mass reproduction of many disease-free spice plants, which are uniform genetically and qualitatively. In recent years, cell and limb suspension (stem and hair roots) have been considered for producing secondary metabolites and for studying the biosynthesis pathway of metabolites. Plant genetic engineering has helped in the genetic identification and manipulation of enzymes of the biosynthetic pathway of secondary metabolites. Gene transformation has improved the production of secondary metabolites that have yield limitations. Molecular markers are powerful tools for accurately identifying important medicinal species, examining genetic diversity, classifying hereditary reserves, and determining their genetic map irrespective of their age, physiological, and environmental conditions. Next-generation sequencing (NGS) methods like restriction-site-associated DNA sequencing (RAD-seq) have revolutionized the study of genetic diversity, and the enzymes and genes implied in the secondary metabolites biosynthetic pathways can be studded by transcriptome profiling (RNA-seq). The ground-breaking genome editing techniques like Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), sequence-specific nucleases of transcription activator-like effector nucleases (TALENs), and zinc-finger nucleases could help in customizing the plants according to the requirements. This article provides an overview of various biotechnology solutions that increase the quality and productivity of spice plants.
Article
Anthocyanins are a class of water-soluble flavonoids, which show a range of pharmacological effects, such as prevention of cardiovascular disease, obesity control and antitumour activity. Their potential antitumour effects are reported to be based on a wide variety of biological activities including antioxidant; anti-inflammation; anti-mutagenesis; induction of differentiation; inhibiting proliferation by modulating signal transduction pathways, inducing cell cycle arrest and stimulating apoptosis or autophagy of cancer cells; anti-invasion; anti-metastasis; reversing drug resistance of cancer cells and increasing their sensitivity to chemotherapy. In this review, the latest progress on the anticancer activities of anthocyanins and the underlying molecular mechanisms is summarized using data from basic research in vitro and in vivo, from clinical trials and taking into account theory and practice. Linked articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.
Article
Ovarian cancer is hard to diagnose and its survival rates dramatically decrease according to the stage progression. Anthocyanidins derived from Kaempferia parviflora has been studied for anti-inflammatory, antioxidant, and anticancer effects in various disease both in vitro and in vivo. However, no studies have evaluated the molecular mechanism of Kaempferia parviflora anthocyanidin fractions in ovarian cancer cells. To study the effects of Kaempferia parviflora anthocyanidins on the progression of ovarian cancer, we extracted anthocyanidins from Kaempferia parviflora and analyzed it using HPLC. Then, we determined the change of cell characteristics by treatment of anthocyanidins derived from Kaempferia parviflora. Based on HPLC analysis, the most abundant anthocyanidins of Kaempferia parviflora was peonidin, followed by cyanidin, delphinidin, and pelargonidin. We selected high-grade serous ovarian cancer and clear cell cancer cell lines to investigate the anticancer effects of anthocyanidin extracts. Treatment with anthocyanidin extracts decreased ES-2 and OV-90 cell proliferation and increased late apoptosis with cell cycle arrest at sub G0/G1 phase. In addition, anthocyanidin extracts hampered the mitochondrial membrane permeability in both cell lines. Moreover, the cytosolic calcium accumulation was detected in ES-2 cells, and the overproduction of reactive oxygen species was estimated in OV-90 cells, respectively. Collectively, these results showed the anticancer effects of Kaempferia parviflora anthocyanidin extracts against the progression of ovarian cancer.
Book
The Chemistry inside Spices & Herbs: Research and Development brings comprehensive information about the chemistry of spices and herbs with a focus on recent research in this field. The book is an extensive 2-part collection of 20 chapters contributed by experts in phytochemistry with the aim to give the reader deep knowledge about phytochemical constituents in herbal plants and their benefits. The contents include reviews on the biochemistry and biotechnology of spices and herbs, herbal medicines, biologically active compounds and their role in therapeutics among other topics. Chapters which highlight natural drugs and their role in different diseases and special plants of clinical significance are also included. Part I focuses on the general aspects of spice biotechnology, structure activity relationships and the natural products that can be used to treat different diseases - such as neurological diseases, inflammation, pain and infections. This part also covers information about phenolic compounds, flavonoids and turmeric supplements. This book is an ideal resource for scholars (in life sciences, phytomedicine and natural product chemistry) and general readers who want to understand the importance of herbs, spices and traditional medicine in pharmaceutical and clinical research.
Article
Lung-cancer is the foremost cause of cancer in humans worldwide, of which 80-85% cases composed of non-small cell lung carcinoma. All treatment decisions depend on the pattern of biomarkers selection to enhance the response to targeted therapies. Although advanced treatments are available for lung-cancer, the disease treatment remains not adequate. There are several synthetic chemotherapeutic agents available for the treatment. However, due to their toxic effect, survival rate is still 15-18%. Besides, medicinal plants are a huge reservoir of natural products that provide protective effects against lung cancer. Likewise, successful studies of potential phytochemicals in targeting lung-cancer biomarkers have created a novel paradigm for the discovery of potent drugs against lung-cancer. Hence, to defeat severe toxicity and resistance towards synthetic drugs, detailed studies are required regarding the available phytochemicals and targets responsible for treatment of lung-cancer. Present review provides comprehensive information about available lung-cancer biomarkers under the classification of predictive, prognostic, and diagnostic type. Moreover, it discusses and enlists phytochemicals with mode of action in different biomarkers, effective doses in in vitro, in vivo, and clinical studies, the limitations associated with usage of phytochemicals as a drug to prevent/cure lung- cancer and the latest techniques employed to overcome such issues.
Article
Blueberries are a popular fruit with an attractive flavor and color, as well as health benefits. These health benefits have been attributed to the important number of bioactive compounds in blueberries with activities such as antioxidant, antitumor, antimutagenic, and antidiabetic effects and the prevention of cardiovascular diseases. Despite these advantages, blueberries are only obtained fresh in certain seasons; therefore, the food and beverage industry transforms them into jelly, puree, or juice. However, the concentration process could help preserve the bioactive compounds of blueberry byproducts. Concentration technologies focus on the removal of excess water to increase the product stability and reduce storage and transportation costs by causing them to take up less space or as a pretreatment before dehydration. These technologies include evaporation, reverse osmosis, and freeze concentration, and each one has different effects on the efficiency, quality, and nutritional value of the final concentrates. However, freeze concentration and reverse osmosis produce a higher‐final quality concentrate than evaporation due to the use of low temperatures, which prevents the loss of thermolabile components such as bioactive compounds. Therefore, this review summarizes the impact of concentration technologies on the bioactive compounds and health benefits of blueberry juice.
Article
With the strengthening of the link between diet and health, several foodstuffs have emerged as possessing potential health benefits such as phenolic rich fruits and vegetables. Blueberries, along with other berries, given their flavonoid and antioxidant content have long since been considered as a particularly interesting health promoting fruit. Therefore, the present work aimed to compile the existing evidences regarding the various potential benefits of blueberry and blueberry based products consumption, giving particular relevance to in vivo works and epidemiological studies whenever available. Overall, the results demonstrate that, while the evidences that support a beneficial role of blueberry and blueberry extracts consumption, further human based studies are still needed.
Chapter
Worldwide, cancer is an illness that affects people of all ages and is quickly becoming a universal epidemic in developing and developed countries. Cancer represents one of the biggest healthcare issues for the human race; thus it demands a proactive strategy for a cure. Humankind has been trying hard to find better, cheaper treatments with fewer side effects to reduce the incidence of the disease and its resulting mortality. Plants are reservoirs for novel chemical entities and provide a promising line for cancer research. For many years, herbal biomolecules (HBs), such as small organic molecules derived naturally from microbes and plants, have provided several useful cancer drugs. HBs or natural products play an important role in cancer prevention and treatment. Plants are crucial sources of HBs and secondary metabolites responsible for their chemopreventive properties and contribute to their activity as apoptosis inducers. For many years, herbal products have been intensively studied, in vitro and in vivo, for their antitumor effects. In recent years, considerably increased uses of these compounds have been discovered. HBs have been identified that significantly contribute to the development of several drugs currently used in cancer chemotherapy. Although many secondary metabolites are known to affect the redox state of the cell, many studies on these compounds have focused on their antioxidant activity instead of on their pro-oxidant and anticancer properties. HBs are more selective in their functions and act specifically on tumor cells without affecting normal cells. Phytochemicals are considered suitable for anticancer drug development due to their epistasis actions on target events with multiple manners. This chapter presents the natural HBs as anticancer agents.
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In this study we investigated the potential effects of a polysaccharide (HDP) from Hedyotis diffusa on the metastasis in human lung adenocarcinoma A549 cells. HDP (25, 50 and 100 μg/ml) significantly suppressed the cell adhesion, invasion and migration of A549 cells in a dose dependent manner by downregulation of matrix metalloproteinase (MMP-2 and MMP-9) and upregulation of tissue inhibitors of metalloproteinase (TIMP-2 and TIMP-9). Moreover, HDP effectively downregulated the protein expressions of epithelial–mesenchymal transition (EMT) markers (N-cadherin and vimentin), and upregulated E-cadherin protein expression, which is involved in interrupting EGFR/Akt/ERK signaling pathways, as well as inhibiting COX-2 protein expression. All these results demonstrated that HDP might be a novel anti-metastatic agent for NSCLC treatment.
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Cancer therapeutic methods comprising chemotherapy, radiotherapy, and surgery are so routine in cancer treatment. Remarkably, there are several personal features which affect the effectiveness of such treatments including nutrition, microbiome diversity, and physical activity which has distinct significant roles during and after therapies along with their bilateral connections. In this way, the ability of gut microbiota36 in modulating the efficacy of chemotherapeutic medications in cancer and other types of disorders is of great importance. In addition, the role of dietary, probiotic, and synthetically engineered bacteria in manipulating and optimizing the gut microbiota is of interest. Conspicuously, the correlation between the commensal microbiota and also host can regulate the physiological activities comprising the immunity system and inflammatory agents and it is scanned in the category of cancers. Bacterial species have been employed in cancer therapy; commensal microbes posse a key beneficial role in this field. Practically, the microbiota has this potential to accelerate and modulates a certain response by priming in order to release the pro-inflammatory agents. We would like to discuss these vital factors in this review as gut microbiota has the potential to be the main option for personalized cancer treatment strategies in the future. Meaning, this novel data present clinical promising feasibilities of modulating cancer therapy with using microbiota.
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Plants over the course of evolution have customized their genomes and produce an enormous variety of specialized phytochemicals termed as secondary metabolites. Secondary metabolites are required by the plants for their interaction with environment and their survival in adverse conditions or stresses. They are derived by unique biosynthetic pathways using primary metabolite and their intermediates. These are mostly synthesized in the cytosol (anthocyanins), chloroplasts (terpenoids), or mitochondria (some amines) but targeted for storage in vacuole for utilization under need. Anthocyanins provide a great economic value for mankind as drugs, food supplement, and dyes. The health benefits of anthocyanins are numerous which have been extrapolated by the scientific community on the basis of their antioxidant capacity. Here potential resources and their role in cancer with biochemical mechanisms have been summarized. The research efforts and accomplishments for the novel anthocyanins and functional food are expected to lead to a sustainable agriculture, health, and environment.
Differentiation from RAW264.7 cells to osteoclasts rely on many signaling pathways, such as NF-κB, MAPK, Akt and others. However, the specific underlying mechanisms are not clear. Recently, much works have focused on the inhibitory effects of plant derived compounds in the differentiation from RAW264.7 to osteoclasts. However, the specific mechanisms remain unclear. In this paper, we summarize a lot of plant derived compounds which exert blocking effect on the progression of differentiation via signaling pathways.
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Anthocyanins are a class of water-soluble flavonoids, which give the intense color to many fruits and vegetables, such as blueberries and red cabbages. Recent studies have shown that anthocyanins have a range of pharmacological properties, such as prevention of cardiovascular disease, improvement of visual functions, obesity control, and anticancer activity. Their potential anticancer effects are reported to be based on a wide variety of biological activities including anti-oxidative stress; anti-inflammation; anti-mutagenesis; induction of differentiation; inhibition of proliferation; cell cycle arrest and apoptosis; anti-invasion; anti-metastasis; anti-angiogenesis and sensitizing cancer cells to chemotherapy. This chapter summarizes the latest developments on the anticancer activities of anthocyanins and anthocyanin-rich extracts in cell culture models, animal cancer models and some clinical trials. Their chemical structures, molecular mechanisms of action in cancer prevention, and in vivo pharmacokinetics-pharmacodynamics (PK-PD) properties will also be discussed.
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Aims Colon cancer (CC) is a prevalent malignancy worldwide and is one of the most easily altered cancers by dietary regulation. Petunidin 3-O-[rhamnopyranosyl-(trans-p-coumaroyl)]-5-O-(β-D-glucopyranoside) (Pt3R5G) isolated and purified from Lycium ruthenicum Murray, which exhibits highly efficient antioxidant activity and specific anticancer effects, is the flavonoids compound. We aimed to study the effect of Pt3R5G on CC cells and elucidate the potential underlying mechanisms. Main methods Cell proliferation was measured by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assays. Cell cycle, cell apoptosis and reactive oxygen species (ROS) analysis were performed by flow cytometry. RNA-sequencing was performed to elucidate the potential underlying mechanisms. The lipid peroxidation level of cells was detected by malondialdehyde (MDA) assay. The mitochondrial morphology of cells was inspected using a transmission electron microscope. Additionally, we overexpressed SLC7A11 to perform rescue experiments. In vivo, xenograft mice assay was performed to verify the effect of Pt3R5G on the growth of colon cancer. Key findings Pt3R5G reduced the cell activity by blocking the cell cycle in G0/G1 phase, inducing the apoptosis and ferroptosis in RKO cells. The overexpressed of SLC7A11, a significantly down-regulated expression gene caused by Pt3R5G, rescued the cell proliferation inhibition and ferroptosis process. Furthermore, Pt3R5G inhibited tumor growth in nude mice. Our study suggests that Pt3R5G inhibits RKO cell proliferation through mainly reducing ferroptosis by down-regulated SLC7A11. Significance As a potential therapeutic drug, Pt3R5G showed efficient anticancer activity through a variety of pathways.
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The AP-1 transcription factor plays a critical role in regulating tumor cell proliferation and has been implicated in controlling a program of gene expression that mediates cell motility and invasion in vitro. We have utilized two dominant negative AP-1 constructs, TAM67 and aFos, each fused to GFP, to investigate the role of AP-1 complexes in an invasive, clinically derived human tumor cell line, HT-1080. As expected, high levels of both GFP-TAM67 and GFP-aFos arrested HT-1080 cells in the G1 phase of the cell cycle. Strikingly, at low levels GFP-aFos, but not GFP-TAM67, caused a change in colony morphology, impairment of directional motility in a monolayer wound healing assay, as well as inhibition of chemotaxis and haptotaxis. Microarray analysis identified a novel set of AP-1 target genes, including the tumor suppressor TSCL-1 and regulators of actin cytoskeletal dynamics, including the gelsolin-like actin capping protein CapG. The demonstration that AP-1 regulates the expression of genes involved in tumor cell motility and cytoskeletal dynamics in a clinically derived human tumor cell line identifies new pathways of control for tumor cell motility.
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A diet containing 5% freeze-dried black raspberries (BRB) markedly inhibits esophageal cancer in rats treated with the carcinogen, N-Nitrosomethylbenzylamine (NMBA). We previously identified esophageal genes that become dysregulated after short-term treatment of rats with NMBA and determined which genes are maintained at near-normal levels of expression if the animals were fed 5% BRB prior to and during NMBA treatment. In this study, we report the effects of the BRB diet on gene expression in esophagi from untreated (control) animals. After 3 wk on a 5% BRB diet, control esophagi were excised, stripped of the submucosal and muscularis layers, and processed for histology and microarray profiling. RNA microarrays revealed that the BRB altered the expression levels of 36 genes; 24 were upregulated, and 12 were downregulated. Among the upregulated genes are genes associated with cellular matrix, signaling cascades, transcription regulation, apoptosis, metabolism, and intriguingly, contraction. Most of the downregulated transcripts are involved in cell regulation, signal transduction, and metabolism. Histopathological analyses revealed that the BRB have little or no effect on esophageal morphology. In conclusion, histological and molecular studies indicate that a 5% BRB diet produces only modest effects on the esophagus, the target tissue for NMBA carcinogenesis in the rat.
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AP-1 is a collection of dimeric sequence specific, DNA binding, transcriptional activators composed of Jun and Fos subunits. The composition, the level and the activity of AP-1 complexes are regulated in response to extracellular stimuli. An important role in this regulation is played by mitogen-activated protein kinases (MAPKs). The specific roles of three MAPKs, namely ERK, JNK and FRK, in modulation of both the level and activity of AP-1, are discussed.
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Degradation of basement membranes and stromal extracellular matrix (ECM) is crucial for invasion and metastasis of malignant cells. Degradation of ECM is initiated by proteinases secreted by different cell types participating in tumor cell invasion, and increased expression or activity of every known class of proteinases (metallo-, serine-, aspartic-, and cysteine) has been linked to malignancy and invasion of tumor cells. Studies performed over the last decade have revealed that matrix metalloproteinases (MMPs) play a crucial role in tumor invasion. Expression of MMP genes is transcriptionally regulated by a variety of extracellular factors including cytokines, growth factors, and cell contact to ECM. This review will summarize the current view on the role of MMPs in tumor growth, invasion, and survival, and focus on the role of mitogen-activated protein kinases and AP-1 and ETS transcription factors in the regulation of MMP gene expression during invasion process.
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Angiogenesis is the process in which new vessels emerge from existing endothelial lined vessels. This is distinct from the process of vasculogenesis in that the endothelial cells arise by proliferation from existing vessels rather than differentiating from stem cells. Angiogenesis is an invasive process that requires proteolysis of the extracellular matrix and, proliferation and migration of endothelial cells, as well as synthesis of new matrix components. During embryonic development, both vasculogenesis and angiogenesis contribute to formation of the circulatory system. In the adult, with the single exception of the reproductive cycle in women, angiogenesis is initiated only in response to a pathologic condition, such as inflammation or hypoxia. The angiogenic response is critical for progression of wound healing and rheumatoid arthritis. Angiogenesis is also a prerequisite for tumor growth and metastasis formation. Therefore, understanding the cellular events involved in angiogenesis and the molecular regulation of these events has enormous clinical implications. This understanding is providing novel therapeutic targets for the treatment of a variety of diseases, including cancer.
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A variety of pathophysiological situations that affect cells of the vasculature, including endothelial and smooth muscle cells, leads to the expression of genes such as adhesion molecules and chemokines that are dependent on members of the nuclear factor (NF)-kappaB family of transcription factors. The corresponding gene products mediate important biological functions such as immune and inflammatory reactions, smooth muscle cell proliferation, and angiogenesis. The beneficial and usually transient NF-kappaB-dependent gene expression may be exaggerated in pathological situations and results in damage to the vessel wall and impaired vascular cell function. In this review, we will capitalize on the favorable and adverse roles of NF-kappaB in the context of vascular disease, eg, chronic and localized inflammation, arteriosclerosis, and neoangiogenesis.
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The influence of white, red and black rice consumption on atherosclerotic plaque formation induced by hypercholesterolemia was investigated in rabbits. Male rabbits (n = 36) were divided into five groups. They were fed a normal laboratory purified diet (normal group, n = 6), a high cholesterol (0.5 g/100 g) diet (HC group, n = 6), a high cholesterol diet with 30 g/100 g white rice (WR group, n = 8), 30 g/100 g red rice (RR group, n = 8), or 30 g/100 g black rice (BR group, n = 8) for 10 wk. Blood samples were collected for lipid measurements and aorta were removed for assessment of atherosclerotic plaques at the end of the protocol. The oxidant and antioxidant status of blood, erythrocytes, liver and aorta was evaluated. The area of atherosclerotic plaque was 50% lower in rabbits fed the red or black rice diets than in those fed the white rice diet. Compared with the HC and WR groups, serum HDL cholesterol and apolipoprotein (apo) A-I concentration were greater (P < 0.05) in the RR and BR groups. Liver reactive oxygen species (ROS) and aortic malondialdehyde (MDA) were significantly lower, and the liver total antioxidative capacity (TAC) and erythrocyte superoxide dismutase (SOD) activity were significantly higher in the RR and BR groups compared with the HC and WR groups. Red or black rice consumption reduced or retarded the progression of atherosclerotic plaque development induced by dietary cholesterol. The enhanced serum HDL cholesterol and apo A-I concentrations, and the increased antioxidant and decreased oxidative status may be mechanisms of the antiatherogenic effect of red or black rice.
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The Akt/protein kinase B (PKB) serine/threonine kinase is well known as an important mediator of many cell survival signaling pathways. Here, we demonstrate for the first time a major role of Akt/PKB in the cell invasion properties of the highly metastatic cell line HT1080. Using confocal microscopic analyses of live samples, we found Akt/PKB to be localized in the leading edge membrane area of migrating HT1080 cells. This localization was dependent on phosphoinositide 3-kinase and required the lipid binding ability of the phosphoinositide binding pleckstrin homology domain of Akt/PKB. We examined the possible function of Akt/PKB in HT1080 invasion. Surprisingly, Akt/PKB potently promoted HT1080 invasion, by increasing cell motility and matrix metalloproteinase-9 (MMP-9) production, in a manner highly dependent on its kinase activity and membrane-translocating ability. The increase in MMP-9 production was mediated by activation of nuclear factor-kappaB transcriptional activity by Akt/PKB. However, Akt/PKB did not affect the cell-cell or cell-matrix adhesion properties of HT1080. Our findings thus establish Akt/PKB as a major factor in the invasive abilities of cancer cells.
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The extracellular matrix (ECM) holds cells together and maintains the three-dimensional structure of the body. It also plays critical roles in cell growth, differentiation, survival and motility. For a tumour cell to metastasize from the primary tumour to other organs, it must locally degrade ECM components that are the physical barriers for cell migration. The key enzymes responsible for ECM breakdown are matrix metalloproteinases (MMPs). To date, 23 MMP genes have been identified in humans and many are implicated in cancer. ECM degradation by MMPs not only enhances tumour invasion, but also affects tumour cell behaviour and leads to cancer progression. This review highlights recent developments with regard to the cellular and molecular mechanisms of MMPs that influence tumour cell growth, invasion and metastasis.
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Approximately 10% of the U.S. population ingests <50% of the current recommended daily allowance for zinc. We investigate the effect of zinc deficiency on DNA damage, expression of DNA-repair enzymes, and downstream signaling events in a cell-culture model. Low zinc inhibited cell growth of rat glioma C6 cells and increased oxidative stress. Low intracellular zinc increased DNA single-strand breaks (comet assay). Zinc-deficient C6 cells also exhibited an increase in the expression of the zinc-containing DNA-repair proteins p53 and apurinic endonuclease (APE). Repletion with zinc restored cell growth and reversed DNA damage. APE is a multifunctional protein that not only repairs DNA but also controls DNA-binding activity of many transcription factors that may be involved in cancer progression. The ability of the transcription factors p53, nuclear factor kappaB, and activator protein 1 (AP1) to bind to consensus DNA sequences was decreased markedly with zinc deficiency, as assayed by electrophoretic mobility-shift assays. Thus, low intracellular zinc status causes oxidative DNA damage and induces DNA-repair protein expression, but binding of p53 and important downstream signals leading to proper DNA repair are lost without zinc.
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The MAPK (mitogen-activated protein kinase) pathway is one of the most important and intensively studied signalling pathways. It is at the heart of a molecular-signalling network that governs the growth, proliferation, differentiation and survival of many, if not all, cell types. It is de-regulated in various diseases, ranging from cancer to immunological, inflammatory and degenerative syndromes, and thus represents an important drug target. Over recent years, the computational or mathematical modelling of biological systems has become increasingly valuable, and there is now a wide variety of mathematical models of the MAPK pathway which have led to some novel insights and predictions as to how this system functions. In the present review we give an overview of the processes involved in modelling a biological system using the popular approach of ordinary differential equations. Focusing on the MAPK pathway, we introduce the features and functions of the pathway itself before comparing the available models and describing what new biological insights they have led to.
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Dietary polyphenols, including anthocyanins, are suggested to be involved in the protective effects of fruits and vegetables against cancer. However, anticancer effects of peonidin 3-glucoside have not been clearly demonstrated, with only limited studies being available concerning the inhibitory effect of cyanidin 3-glucoside for tumor cell growth. Therefore, in this study, we have isolated and identified the two bioactive compounds, peonidin 3-glucoside and cyanidin 3-glucoside, from Oryza sativa L. indica, to treat various cancer cells. The results showed that, among analyzed cell lines, HS578T was the most sensitive to peonidin 3-glucoside and cyanidin 3-glucoside. Treatment with peonidin 3-glucoside or cyanidin 3-glucoside resulted in a strong inhibitory effect on cell growth via G2/M arrest. Regarding cell cyclerelated proteins, peonidin 3-glucoside treatment resulted in down-regulation of protein levels of cyclin-dependent kinase (CDK)-1, CDK-2, cyclin B1, and cyclin E, whereas cyanidin 3-glucoside could decrease the protein levels of CDK-1, CDK-2, cyclin B1, and cyclin D1. In addition, cyanidin 3-glucoside or peonidin 3-glucoside also induced caspase-3 activation, chromatin condensation, and cell death. Furthermore, anthocyanins from O. sativa L. indica were evidenced by their inhibition on the growth of Lewis lung carcinoma cells in vivo.
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The expression of urokinase-type plasminogen activator (u-PA), its receptor (u-PAR) and metalloproteases activity were analyzed in 4 human gastric-cancer cell lines (AGS, Hs746T, SNU-1, and SNU-5), in an attempt to relate these activities to their invasive potential and tumorigenicity on the modified chorioallantoic membranes (CAM) of chick embryos. Only 1 of the 4 cell lines tested, Hs746T, expressed both u-PA and u-PAR as well as MMP-2, but not MMP-9. This cell line was both tumorigenic and highly invasive (51.3 ± 13.1%) on a modified CAM. Its invasive capacity was comparable with that of a highly malignant human epidermoid-carcinoma cell line (HEp3), which usually showed 40 to 50% invasiveness. The 3 other cell lines all produced MMP-2 and MMP-9, but only AGS showed moderate invasiveness (24.2 ± 8.8%). While antibodies to u-PA were significantly effective in reducing CAM invasiveness of Hs746T cells by approximately 40%, the invasiveness of the t-PA-expressing AGS cell line was not affected by anti-t-PA antibodies. These results suggest that when one of the components of the u-PA/u-PAR system (the enzyme and/or the receptor) is not produced and u-PA/u-PAR-dependent cell-surface proteolytic activity is thereby diminished, the malignant phenotype that can be determined by tumorigenicity and invasion of connective tissue on a CAM is compromised. Production of both type-IV collagenases (MMP-2 and MMP-9) cannot offset this deficiency.Int. J. Cancer 71: 867-873, 1997. © 1997 Wiley-Liss Inc.
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Epidemiological studies have described the beneficial effects of dietary polyphenols (flavonoids) on the reduction of the risk of chronic diseases, including cancer. Moreover, it has been shown that flavonoids, such as quercetin in apples, epigallocatechin-3-gallate in green tea and genistein in soya, induce apoptosis. This programmed cell death plays a critical role in physiological functions, but there is underlying dysregulation of apoptosis in numerous pathological situations such as Parkinson's disease, Alzheimer's disease and cancer. At the molecular level, flavonoids have been reported to modulate a number of key elements in cellular signal transduction pathways linked to the apoptotic process (caspases and bcl-2 genes), but that regulation and induction of apoptosis are unclear. The aim of this review is to provide insights into the molecular basis of the potential chemopreventive activities of representative flavonoids, with emphasis on their ability to control intracellular signaling cascades responsible for regulating apoptosis, a relevant target in cancer-preventive approach.
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Eicosanoids modulate the interaction of tumor cells with various host components in cancer metastasis. Their synthesis involves the release of arachidonic acid (AA) from cellular phospholipids by phospholipase A2 (PLA2), followed by metabolism by cyclooxygenases (COXs) and lipooxygenases (LOXs). This study aimed to identify the pathway(s) of AA metabolism that are required for the invasion of prostate tumor cells. DU-145 and PC-3 human prostate cancer cell lines were used to test the effect of inhibitors of PLA2, COX, or LOX on the invasion of prostate tumor cells through Matrigel in vitro using the Boyden chamber assay and fibroblast-conditioned medium as the chemoattractant. We used nontoxic doses that did not inhibit simple cell motility and did not decrease clonogenic survival. All of the inhibitors caused a significant reduction in AA release from treated cells compared with control cells, which indicated that the treatments were biochemically active. Invasion through Matrigel was inhibited by the PLA2 inhibitor 4-bromophenacyl bromide (4-BPB), the general COX inhibitor ibuprofen (IB), and the highly selective COX-2 inhibitor NS398. Inhibition of cell invasiveness by 4-BPB (1.0 microM), IB (10.0 microM), and NS398 (10.0 microM) was reversed by the addition of prostaglandin E2 (PGE2). PGE2 alone, however, did not stimulate invasiveness, which suggests that its production is necessary for rendering the cells invasive-permissive but not sufficient for inducing invasiveness. In contrast, we found no significant inhibition of invasion of prostate tumor cells treated with esculetin (1.0 microM) or nordihydroguiaretic acid (1.0 microM), which are specific inhibitors of LOX. We also tested the effect of 4-BPB, IB, NS398, and esculetin on the secretion of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), as key enzymes in the proteolysis of Matrigel during invasion, using gelatin zymograms and Western blots. Cells that received 4-BPB, IB, or NS398, but not esculetin showed a significant reduction in the levels of proMMP-2, MMP-9, and proMMP-9 in the culture medium. DU-145 cells did not secrete TIMP-1, and the drugs did not alter the secretion of TIMP-2. This work highlights the role played by COX in disturbing the balance between MMPs and TIMPs in prostate cancer cells, and it points to the potential use of COX inibitors, especially COX-2 selective inhibitors, in the prevention and therapy of prostate cancer invasion.
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Beginning with its discovery in 1986 and continuing through the present, the transcription factor NF-κB has attracted widespread interest based on its unusual regulation, the variety of stimuli that activate it, the diverse genes and biological responses that it controls, the striking evolutionary conservation of structure and function among family members, and its apparent involvement in a variety of human diseases (Table (Table1).1). Importantly, and consistent with the last point, NF-κB has been shown to be the target of several anti-inflammatory and anticancer drugs.
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Proteases are linked to the malignant phenotype of different solid tumors. Therefore, the expression of the matrix metalloproteinase (MMP)-2 and MMP-9 and of the serine protease urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) in the progression of ovarian cancer was investigated. Gelatinolytic activity and protein expression of MMP-2 and MMP-9 were analyzed in tissue extracts of 19 cystadenomas and 18 low malignant potential (LMP) tumors, as well as 41 primary tumors of advanced ovarian cancer stage International Federation of Gynecology and Obstetrics IIIc/IV and their corresponding omentum metastases by quantitative gelatin zymography and Western blot. In the same tissue extracts, antigen levels of uPA and its inhibitor PAI-1 were determined by ELISA. Protein expression of pro-MMP-2 (72 kDa) and pro-MMP-9 (92 kDa as well as antigen levels of uPA and PAI-1 were low in benign ovarian tumors but increased significantly from LMP tumors to advanced ovarian cancers. The highest values of all of the proteolytic factors were detected in omentum metastases. Active MMP-2 enzyme (62 kDa) was detected only in ovarian cancer (66%) and corresponding metastases (93%) but never in benign or LMP tumors. The activation rate of MMP-2 to its active isoform was higher in the metastases. Comparing both proteolytic systems, higher PAI-1 concentrations were consistently found in cancers with high pro-MMP-9 expression. These data indicate that members of the plasminogen activator system, as well as the metalloproteinases MMP-2/9, increase with growing malignant potential of ovarian tumors. These findings are of particular relevance to the development of protease inhibitors as new therapeutic approaches in ovarian cancer.
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Antioxidant activity was studied for anthocyanins extracted from purple black rice (PBR) by a 3% aqueous trifluoroacetic acid solution (TFA), as well as for anthocyanins extracted from blueberry (Bluetta, high bush type). Capillary zone electrophoresis revealed that the PBR extract contained almost exclusively a single anthocyanin, which was identified as cyanidin 3-O-beta-D-glucoside (Cy 3-Glc) after purification by polyvinylpyrrolidone column chromatography. In contrast, 11 anthocyanins were identified in the blueberry extract. PBR extract showed slightly weaker superoxide scavenging and crocin bleaching activities than blueberry extract did. Both PBR and blueberry extracts, however, showed 10 to 25 times stronger activity than the same concentration of Trolox used as a reference antioxidant. It was further noted that the purified Cy 3-Glc from PBR extract retained approximately 74% of the antioxidant activity (both crocin bleaching and superoxide scavenging) observed in the original TFA extract. The hydroxyl radical scavenging activity of both extracts was several times weaker than that of the same concentration of Trolox, although the PBR extract showed approximately two times stronger activity than blueberry extract did. The hydroxyl radical scavenging activity of the purified Cy 3-Glc from PBR, however, decreased to approximately 20% of that of the original PBR extract. These results indicate that the anthocyanin Cy 3-Glc contributes to the antioxidant activity of PBR through its strong superoxide radical but not hydroxyl radical scavenging activity.
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The invasive nature of brain-tumour cells makes an important contribution to the ineffectiveness of current treatment modalities, as the remaining tumour cells inevitably infiltrate the surrounding normal brain tissue, which leads to tumour recurrence. Such local invasion remains an important cause of mortality and underscores the need to understand in more detail the mechanisms of tumour invasiveness. Several proteases influence the malignant characteristics of gliomas--could their inhibition prove to be a useful therapeutic strategy?
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Anthocyanins, present in fruits and vegetables as natural colorants, have been well characterized to possess bioactive properties. Anthocyanin components extracted from black rice (Oryza sativa L. indica) separated by gel filtration and identified using LC-MS were cyanidin 3-glucoside and peonidin 3-glucoside. A standardized extract of black rice pigmented fraction (BRE) containing known proportions of cyanidin 3-glucoside and peonidin 3-glucoside exhibited marked antioxidant activities and free radical scavenging capacities in a battery of in vitro model systems. Significant (p < 0.05) prevention of supercoiled DNA strand scission induced by reactive oxygen species (specifically, peroxyl radical and hydroxyl radicals) and suppression of the oxidative modification of human low-density lipoprotein was obtained with BRE. In addition, BRE reduced (p < 0.05) the formation of nitric oxide by suppressing inducible nitric oxide synthase expression in murine macrophage RAW264.7 cells, without introducing cell toxicity. The results of this study show that black rice contains anthocyanin pigments with notable antioxidant and anti-inflammatory properties for potential use in nutraceutical or functional food formulations.
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Significant emphasis is being placed on combination chemotherapy of cancer using cytotoxic agents and naturally occurring chemopreventive agents, having different mechanisms of action with non-overlapping toxicity. In this regard, here we assessed whether a cancer preventive agent silibinin synergizes the therapeutic potential of doxorubicin (Dox), cisplatin or carboplatin, the chemotherapeutic drugs, in both estrogen-dependent and -independent human breast carcinoma, MCF-7 and MDA-MB468 cells, respectively. When tested alone, each of the four agents showed growth inhibition in both the cell lines in a dose- and a time-dependent manner. Based on their growth inhibitory effects, several combinations of silibinin (25-100 microM) with Dox (10-75 nM), cisplatin (0.2-2 microg/ml) or carboplatin (2-20 microg/ml) were next assessed for their synergistic, additive and/or antagonistic efficacy towards cell growth inhibition and apoptotic death. The strongest synergistic effects for cell growth inhibition [combination index (CI) 0.35 for MCF-7 and 0.45 for MDA-MB468 cells] were evident at a silibinin dose of 100 microM plus 25 nM Dox, in both the cell lines. Most of the CIs for other combinations of these three drugs with silibinin also suggested strong synergistic effects for cell growth inhibition in both MCF-7 and MDA-MB468 cells. In quantitative apoptosis studies, combination of silibinin with Dox resulted in much stronger apoptotic death compared to each agent alone in both cell lines. In case of silibinin combination with cisplatin, it showed no additional apoptotic effect in either cell line. Similarly, silibinin plus carboplatin combination showed stronger apoptotic effect only in MCF-7 cells. Together, these results suggest a possible synergism between silibinin and conventional cytotoxic agents for breast cancer treatment, and warrant further in vivo studies in pre-clinical breast cancer models.
Article
Oryza sativa cv. Heugjinjubyeo (Gramineae), anthocyanin-pigmented rice, having dark purple grains, is known broadly as enriched rice with an improved taste. Two bioactive compounds were isolated from the 0.5% HCl-ethyl alcohol soluble fraction of the aleurone layer of O. sativa cv. Heugjinjubyeo through an activity-monitored fractionation and isolation method. From spectral analysis, the cytotoxic components were the anthocyanidins cyanidin (1) and malvidin (2) The 50% growth inhibitory concentrations (IC(50)) of cyanidin and malvidin on U937, human monocytic leukemia cells, were 60 and 40 microg/mL, respectively. These compounds showed cytotoxicity through the arrest of the G(2)/M phase of cell cycle and induction of apoptosis.
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The urokinase plasminogen activator (uPA) system consists of the serine protease uPA, the glycolipid-anchored receptor, uPAR, and the 2 serpin inhibitors, plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2). Recent findings suggest that uPA, uPAR and PAI-1 play a critical role in cancer invasion and metastasis. Consistent with their role in cancer dissemination, high levels of uPA, PAI-1 and uPAR in multiple cancer types correlate with adverse patient outcome. The prognostic value of uPA/PAI-1 in axillary node-negative breast cancer patients was recently validated using both a prospective randomised trial and a pooled analysis. Assay of uPA and PAI-1 may thus help identify low-risk node-negative patients for whom adjuvant chemotherapy is unnecessary. Finally, emerging data suggest that high levels of uPA and PAI-1 in breast cancer are associated with a preferential response to adjuvant chemotherapy but relative resistance to hormone therapy. The measurement of uPA components, especially in breast cancer, thus has the potential to help with individualised patient management.
Article
In this study, we assessed the ability of erythropoietin (EPO) to synergize with various chemotherapeutic agents and suppress the growth and metastasis of solid tumors. Animals were inoculated with Lewis lung carcinoma (LLC) cells and treated with EPO alone, the designated chemotherapeutic drug (cisplatin, mitomycin C or cyclophoshamide) alone, or EPO and the drug. Tumor volume was monitored daily. Thirteen days following cell injection, tumor mass was determined. In addition, the number of the metastatic foci in the lungs was determined. Cisplatin alone was capable of inducing a 7-fold decrease in final tumor volume compared to tumor-bearing animals injected with saline. However, when EPO was combined with cisplatin, the animals experienced an 11-fold reduction in final tumor volume compared to saline-injected animals (P<0.001). A 2.5-fold reduction in tumor mass was observed in animals treated with cisplatin, compared to the saline-injected groups. Furthermore, injections of EPO and cisplatin induced a 4-fold reduction in tumor mass (P<0.001). Blood analysis indicated that a significant increase of more than 30% in WBC was found in animals injected concurrently with cisplatin and EPO, as compared to saline-injected mice (P<0.03). When EPO and mitomycin C were injected together, tumor mass was further reduced by 14% compared to that seen in mice treated with mitomycin C alone. However, this difference was not statistically significant. We conclude from this study that EPO can synergize with chemotherapeutic agents to further suppress the growth of tumors. The level of synergism is drug related.
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Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,372,910 new cancer cases and 570,280 deaths are expected in the United States in 2005. When deaths are aggregated by age, cancer has surpassed heart disease as the leading cause of death for persons younger than 85 since 1999. When adjusted to delayed reporting, cancer incidence rates stabilized in men from 1995 through 2001 but continued to increase by 0.3% per year from 1987 through 2001 in women. The death rate from all cancers combined has decreased by 1.5% per year since 1993 among men and by 0.8% per year since 1992 among women. The mortality rate has also continued to decrease from the three most common cancer sites in men (lung and bronchus, colon and rectum, and prostate) and from breast and colorectal cancers in women. Lung cancer mortality among women has leveled off after increasing for many decades. In analyses by race and ethnicity, African American men and women have 40% and 20% higher death rates from all cancers combined than White men and women, respectively. Cancer incidence and death rates are lower in other racial and ethnic groups than in Whites and African Americans for all sites combined and for the four major cancer sites. However, these groups generally have higher rates for stomach, liver, and cervical cancers than Whites. Furthermore, minority populations are more likely to be diagnosed with advanced stage disease than are Whites. Progress in reducing the burden of suffering and death from cancer can be accelerated by applying existing cancer control knowledge across all segments of the population.
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The movement of cancer cells into tissue surrounding the tumour and the vasculature is the first step in the spread of metastatic cancers. Recent advances in imaging, the use of 3D model systems and the application of microarray technologies have yielded new insights into these processes. This work has challenged our views about what causes cancer cells to become motile in the first place, and has demonstrated that cancer cells can move in many different ways.
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Anthocyanins are naturally occurring reddish pigments that abundant in fruits and vegetables. To investigate the mechanistic basis for the anti-tumor properties of anthocyanins, five aglycone (cyanidin, delphinidin, malvidin, pelargonidin, and peonidin) and four glycosylated (cyanidin-3-glucoside, malvidin-3-glucoside, pelargonidin-3-glucoside and peonidin-3-glucoside) anthocyanins were used to examine their effects on cell cycle progression and induction of apoptosis in human gastric adenocarcinoma AGS cells. The data from cell viability assay showed that malvidin exhibited the most potent anti-proliferation effect on AGS cells in a time- and dose-dependent manner (P<0.05). This event is accompanied the arrest of AGS cells at the G0/G1 phase by malvidin at the tested concentrations of 0-200 microM. Cellular uptake of anthocyanin and anthocyanidin was confirmed by HPLC analysis and the intracellular accumulation of malvidin (24.9+/-1.1 microM/mg protein) was observed when treatment of AGS cells with malvidin for 12 h. In addition, an accumulation of AGS cells in sub-G1 phase (20% and 30% increase for 100 and 200 microM of malvidin, respectively) was observed as well as by the appearance of a fraction of cells with an aneudiploid DNA content. The occurrence of apoptosis induced by malvidin was confirmed by morphological and biochemical features, including apoptotic bodies formation, caspase-3 activation and poly(ADP-ribose) polymerase proteolysis. Furthermore, the mitochondrial membrane potential of apoptotic cells after treatment with malvidin was significantly lost and resulted in the elevation of Bax/Bcl-2 ratio for 1.6-fold against control for 100 microM treatment. In addition, the malvidin treatment significantly increased the p38 kinase expression and inhibited the ERK activity, and the effects of malvidin on caspase-3 activation were blocked, respectively, by the ERK and p38 inhibitors. These findings suggest that growth inhibition and cytotoxicity of AGS cells by malvidin is involved in the induction of apoptosis rather than necrosis.
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Silibinin, isolated from Silybum marianum, has been known for its hepatoprotective properties and recent studies have revealed its antiproliferative and apoptotic effects on several cancer cells. An inhibitory effect of silibinin on tumor invasion and matrix metalloproteinase-2 (MMP-2) and urokinasetype plasminogen activator (u-PA) activities in culture medium has been observed in our previous study and the impacts of silibinin on enzyme activities of MMPs, u-PA, mitogen-activated protein kinase (MAPK) and Akt in A549 cells were continued to explore in this study. Our results showed that silibinin exerted an inhibitory effect on the phosphorylation of Akt, as well as extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are the members of the MAPK family involved in the up-regulation of MMPs or u-PA, while no effects on the activities of p38(MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase were observed. A treatment with silibinin to A549 cells also led to a dose-dependent inhibition on the activation of NF-kappaB, c-Jun and c-Fos. Additionally, the treatment of inhibitors specific for MEK (U0126) or PI3K (LY294002) to A549 cells could result in a reduced expression of MMP-2 and u-PA concomitantly with a marked inhibition on cell invasion. These findings suggested that the inhibition on MMP-2 and u-PA expression by silibinin may be through a suppression on ERK1/2 or Akt phosphorylation, which in turn led to the reduced invasiness of the cancer cells.
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Akt, a downstream mediator of phosphatidylinositol 3-kinase (PI3K), is a signal transduction protein that plays a central role in tumorigenesis. The tumor suppressor gene PTEN negatively regulates the PI3K/Akt signaling pathway. However, the roles of Akt and PTEN function in patients with non-small cell lung cancer (NSCLC) is not well established. To clarify roles of expression of phosphorylated Akt (p-Akt) and loss of PTEN expression in biological behavior and prognosis of NSCLC. Immunohistochemical staining was used to determine the expression of p-Akt and PTEN in 20 cases of normal lung tissues and 102 cases patients with NSCLC. All patients with NSCLC were followed from 3 to 60 months. The positive incidence of p-Akt expression and loss incidence of PTEN expression in NSCLC were 41.2% (42/102) and 46.1% (47/102), while negative of p-Akt expression (0%, 0/20) and positive of PTEN expression (100%, 20/20) in normal lung tissues. Overexpression of p-Akt and loss of PTEN expression were correlated to poor differentiation, lymph node involvement, distant metastasis and late stages. A significant negative correlation was observed between expression of p-Akt and PTEN (r = -0.425, P < 0.001). Patients with p-Akt positive expression (42/102) and loss of PTEN expression (47/102) showed significantly worse 5 years survival rate and median survival time than relevant those with p-Akt negative expression (14.29% versus 33.33%, 14 months versus 32 months, Log-rank test X(2) = 14.24, P < 0.001) and PTEN positive expression (10.64% versus 38.18%, 15 months versus 40 months, Log-rank test X(2) = 21.06, P < 0.001). A univariate analysis revealed that smoking, tumor size, lymph node involvement, distant metastasis, stage, p-Akt and loss of PTEN expression were significant correlative factors with prognosis. The result of multivariate Cox analysis showed that smoking, stage and loss of PTEN expression were independent prognosticators. p-Akt is overexpressed and accompanied by the loss of PTEN in clinical specimens of NSCLC. Both p-Akt and PTEN are concerned with invasion and metastasis of NSCLC. Loss of PTEN expression is an independent poor prognostic factor for patients with NSCLC.