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β-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation
Abstract
Both PI3K/AKT/mTOR/S6K1 and mitogen activated protein kinase (MAPK) signaling cascades play an important role in cell proliferation, survival, angiogenesis, and metastasis of tumor cells. In the present report, we investigated the effects of β-caryophyllene oxide (CPO), a sesquiterpene isolated from essential oils of medicinal plants such as guava (Psidium guajava), oregano (Origanum vulgare L.), cinnamon (Cinnamomum spp.) clove (Eugenia caryophyllata), and black pepper (Piper nigrum L.) on the PI3K/AKT/mTOR/S6K1 and MAPK activation pathways in human prostate and breast cancer cells. We found that CPO not only inhibited the constitutive activation of PI3K/AKT/mTOR/S6K1 signaling cascade; but also caused the activation of ERK, JNK, and p38 MAPK in tumor cells. CPO induced increased reactive oxygen species (ROS) generation from mitochondria, which is associated with the induction of apoptosis as characterized by positive Annexin V binding and TUNEL staining, loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase-3, and cleavage of PARP. Inhibition of ROS generation by N-acetylcysteine (NAC) significantly prevented CPO-induced apoptosis. Subsequently, CPO also down-regulated the expression of various downstream gene products that mediate cell proliferation (cyclin D1), survival (bcl-2, bcl-xL, survivin, IAP-1, and IAP-2), metastasis (COX-2), angiogenesis (VEGF), and increased the expression of p53 and p21. Interestingly, we also observed that CPO can significantly potentiate the apoptotic effects of various pharmacological PI3K/AKT inhibitors when employed in combination in tumor cells. Overall, these findings suggest that CPO can interfere with multiple signaling cascades involved in tumorigenesis and used as a potential therapeutic candidate for both the prevention and treatment of cancer.
... However, one study supports our findings, as CO was shown to have a dose-dependent effect on HCCLM3 cell-induced tumors (adult hepatocellular carcinoma) [49]. Nevertheless, there are several studies demonstrating the anticancer activity of CO in some cancer cell lines, such as human lung cancer (A549) [50], human prostate cancer (PC-3) [51], and breast cancer (MCF-7) [52]. It is important to point out some limitations of our in vivo model; the interactions of the human tumor microenvironment are not well established, the variability in the in vivo response is due to the biological complexity of tumor models, and the rate of cell proliferation. ...
... For the generation of necrosis, we believe it is due to the concentration and cell type. Some reports report that CO generated a significant increase in the cell population in early and late apoptosis, studies that were carried out in the cell lines HeLa, HepG2, AGS, SNU-1, SNU-169 [44], PC-3 [51,52], MCF-7 [51] using concentrations of 3-50 µM and 24 h of exposure; and in another report reports the significant increase in the cell population in early, late apoptosis, and necrosis in A549 cell lines [50] using concentrations below 3 µM and 24 h of exposure. In most studies, significant induction of apoptosis was associated, through upregulation of caspase 3, 7, and 9 expressions, as well as Bax, and downregulation of Bcl-2, loss of mitochondrial membrane potential, cytochrome c release, and PARP cleavage [50,51]. ...
... For the generation of necrosis, we believe it is due to the concentration and cell type. Some reports report that CO generated a significant increase in the cell population in early and late apoptosis, studies that were carried out in the cell lines HeLa, HepG2, AGS, SNU-1, SNU-169 [44], PC-3 [51,52], MCF-7 [51] using concentrations of 3-50 µM and 24 h of exposure; and in another report reports the significant increase in the cell population in early, late apoptosis, and necrosis in A549 cell lines [50] using concentrations below 3 µM and 24 h of exposure. In most studies, significant induction of apoptosis was associated, through upregulation of caspase 3, 7, and 9 expressions, as well as Bax, and downregulation of Bcl-2, loss of mitochondrial membrane potential, cytochrome c release, and PARP cleavage [50,51]. ...
The Annona genus contains some species used in Mexican traditional medicine for the treatment cancer, including Annona macroprophyllata (A. macroprophyllata). The present study aimed to investigate the anticancer activity of caryophyllene oxide (CO) isolated from A. macroprophyllata using in vivo, in vitro, and in silico approaches. The identification of CO was performed using gas chromatography-mass spectroscopy and NMR methods. Antilymphoma activity was evaluated in male and female Balb/c mice inoculated with U-937 cells. Cytotoxic activity was evaluated using the WST method and flow cytometry was used to determine the type of cell death. Acute oral toxicity was determined, and a molecular docking study was performed using target proteins associated with cancer, including, HMG-CoA, Bcl-2, Mcl-1, and VEGFR-2. Results showed that CO exhibited significant antilymphoma and cytotoxic activities, and its effects were comparable to MTX. In addition, flow cytometry showed that the anticancer activity of CO could be mediated by the induction of late apoptosis and necrosis. The result for the acute oral toxicity of CO was classified in category 4, suggesting it is low risk. Finally, molecular coupling studies showed that CO had more affinity for the enzymes HMG-CoA reductase and Bcl-2. Our study provides evidences that CO is a potential anticancer agent for the treatment of histiocytic lymphoma.
... The antioxidant capacity of I. viscosa extracts and fractions was performed following the methodology outlined by Brand-Williams et al. [48]. Different concentrations (0. 25,50,100,150,250,350,450, or 750 µg/mL) of I. viscosa extracts or fractions were mixed with an equal volume of a 0.5 mM solution of 2,2-Diphenyl-1-picrylhydrazyl (DPPH; ref D9132, Sigma-Aldrich, St. Louis, MO, USA) in methanol. The mixture was left to react in the dark for 30 min at room temperature, and absorbance was measured at 517 nm using a spectrophotometer. ...
... Betulin, another triterpenoid present in the IVL DCM fraction, was reported to have anticancer effects [97,98]. Caryophyllene oxide is an oxygenated sesquiterpene that has been documented to have important anticancer activities, impacting the growth and proliferation of various cancer cells [99][100][101][102][103]. Isopulegol is a monoterpene that has exhibited in vitro cytotoxic effects against several cancer cell lines [104,105]. ...
... For example, I. viscosa sesquiterpene lactones can inhibit the growth and metastasis of human cancer cells, induce apoptosis, autophagy, and cell cycle arrest, and increase the sensitivity of chemotherapy drugs, activate the p38 MAPK pathway, and inhibit the NF-κB pathway in lung cancer [115]. In addition, several terpenoids that we identified in the IVL DCM fraction are known to induce apoptosis [94][95][96][97][98][99][100][101][102][103][104][105]. For instance, caryophyllene oxide has been shown to induce apoptosis of A549 cells [99] and has been reported to induce apoptosis through the PI3K/AKT/mTOR/S6K1 pathway [101]. ...
Simple Summary
Inula viscosa (synonymous of Dittrichia viscosa) is a plant used in traditional Mediterranean and Middle Eastern medicine to manage various illnesses. While it has shown anticancer effects against various cancer cell lines, its impact on lung cancer has not been under extensive study. This research explored the potential of the methanolic and aqueous extracts and a terpenoid-rich fraction of I. viscosa leaves and stems against human lung cancer cells. We found that the methanolic extract of I. viscosa leaves was particularly effective in reducing the viability of lung cancer cells in vitro, and other cancer cell types, without affecting normal cells. The terpenoid-rich fraction demonstrated anticancer properties by attenuating the levels of proliferation marker proteins, activating the intrinsic apoptosis pathway, and inhibiting cell migration. GC/MS analysis revealed that the terpenoid-rich fraction encompasses several metabolites that can substantiate its biological activities.
Abstract
Inula viscosa is a widely used plant in traditional Mediterranean and Middle Eastern medicine for various illnesses. I. viscosa has been shown to have anticancer effects against various cancers, but its effects against lung cancer have been under limited investigation. At the same time, I. viscosa is rich in terpenoids whose anti-lung cancer effects have been poorly investigated. This study aimed to examine the potential anticancer properties of methanolic and aqueous extracts of stems and leaves of I. viscosa and its terpenoid-rich fraction against human lung cancer A549 cells. Results showed that the methanolic extracts of I. viscosa had significantly higher polyphenol and flavonoid content and radical scavenging capacity than the aqueous extracts. In addition, leaves methanolic extracts (IVLM) caused the highest reduction in viability of A549 cells among all the extracts. IVLM also reduced the viability of human ovarian SK-OV-3, breast MCF-7, liver HepG2, and colorectal HCT116 cancer cells. A terpenoid-rich I. viscosa fraction (IVL DCM), prepared by liquid-liquid separation of IVLM in dichloromethane (DCM), displayed a substantial reduction in the viability of A549 cells (IC50 = 27.8 ± 1.5 µg/mL at 48 h) and the panel of tested cancerous cell lines but was not cytotoxic to normal human embryonic fibroblasts (HDFn). The assessment of IVL DCM phytochemical constituents using GC-MS analysis revealed 21 metabolites, highlighting an enrichment in terpenoids, such as lupeol and its derivatives, caryophyllene oxide, betulin, and isopulegol, known to exhibit proapoptotic and antimetastatic functions. IVL DCM also showed robust antioxidant capacity and decent polyphenol and flavonoid contents. Furthermore, Western blotting analysis indicated that IVL DCM reduced proliferation (reduction of proliferation marker Ki67 and induction of proliferation inhibitor proteins P21 and P27), contaminant with P38 MAP kinase activation, and induced the intrinsic apoptotic pathway (P53/BCL2/BAX/Caspase3/PARP) in A549 cells. IVL DCM also reduced the migration of A549 cells, potentially by reducing FAK activation. Future identification of anticancer metabolites of IVL DCM, especially terpenoids, is recommended. These data place I. viscosa as a new resource of herbal anticancer agents.
... β-caryophyllene oxide (CPO) is a sesquiterpene ( Figure 1A) isolated from the essential oils of medicinal plants such as guava (Psidium guajava), cinnamon (Cinnamomum spp.), oregano (Origanum vulgare L.), black pepper (Piper nigrum L.), and clove (Eugenia caryophyllata). CPO has a wide range of pharmacological effects, including antibacterial, antifungal, immunomodulatory, anti-inflammatory, antirheumatic, and antioxidant properties [2]. Importantly, CPO has emerged as a promising anticancer compound because it primarily inhibits prostate, breast, and multiple myeloma cancer cell proliferation, angiogenesis, and metastasis by blocking Akt/mTOR/S6K1 and STAT3 signaling pathways and triggering apoptosis through reactive oxygen species (ROS) and MAPK activation [2,3]. ...
... CPO has a wide range of pharmacological effects, including antibacterial, antifungal, immunomodulatory, anti-inflammatory, antirheumatic, and antioxidant properties [2]. Importantly, CPO has emerged as a promising anticancer compound because it primarily inhibits prostate, breast, and multiple myeloma cancer cell proliferation, angiogenesis, and metastasis by blocking Akt/mTOR/S6K1 and STAT3 signaling pathways and triggering apoptosis through reactive oxygen species (ROS) and MAPK activation [2,3]. Moreover, CPO stimulates apoptosis in lung cancer cells through mitochondrial stress, cell cycle arrest, and DNA fragmentation [4,5]. ...
... CPO has been shown to exert a broad spectrum of pharmacological effects, not only through inhibiting the proliferation of various tumor cell types, but also by being an antimicrobial, anti-inflammatory, and an antirheumatic agent [2] that targets a vast array of intracellular networks. One of the essential characteristics of potential cancer therapeutics is the lack of toxicity to off-target tissue, most notably RBCs, to circumvent the complexities that may arise due to chemotherapy-associated anemia. ...
Background: Eryptosis stimulated by anticancer drugs can lead to anemia in patients. β-caryophyllene oxide (CPO) is an anticancer sesquiterpene present in various plants; however, its effect on the structure and function of human red blood cells (RBCs) remains unexplored. The aim of this study was to investigate the hemolytic and eryptotic activities and underlying molecular mechanisms of CPO in human RBCs. Methods: Cells were treated with 10–100 μM of CPO for 24 h at 37 °C, and hemolysis, LDH, AST, and AChE activities were photometrically assayed. Flow cytometry was employed to determine changes in cell volume from FSC, phosphatidylserine (PS) externalization by annexin-V-FITC, intracellular calcium by Fluo4/AM, and oxidative stress by 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA). Cells were also cotreated with CPO and specific signaling inhibitors and antihemolytic agents. Furthermore, whole blood was exposed to CPO to assess its toxicity to other peripheral blood cells. Results: CPO induced concentration-responsive hemolysis with LDH and AST leakage, in addition to PS exposure, cell shrinkage, Ca²⁺ accumulation, oxidative stress, and reduced AChE activity. The toxicity of CPO was ameliorated by D4476, staurosporin, and necrosulfonamide. ATP and PEG 8000 protected the cells from hemolysis, while urea and isotonic sucrose had opposite effects. Conclusions: CPO stimulates hemolysis and eryptosis through energy depletion, Ca²⁺ buildup, oxidative stress, and the signaling mediators casein kinase 1α, protein kinase C, and mixed lineage kinase domain-like pseudokinase. Development of CPO as an anticancer therapeutic must be approached with prudence to mitigate adverse effects on RBCs using eryptosis inhibitors, Ca²⁺ channel blockers, and antioxidants.
... Betulin, another triterpenoid present in the IVL DCM fraction, was reported to have anticancerous effects [98,99]. Caryophyllene oxide is an oxygenated sesquiterpene that has been documented to have important anticancer activities, impacting the growth and proliferation of various cancer cells [100][101][102][103][104]. Isopulegol is a monoterpene that has exhibited in vitro cytotoxic effects against several cancer cell lines [105,106]. ...
... For example, I. viscosa sesquiterpene lactones can inhibit the growth and metastasis of human cancer cells, induce apoptosis, autophagy, and cell cycle arrest, and increase the sensitivity of chemotherapy drugs, activate the p38 MAPK pathway and inhibit NF-κB pathway in lung cancer [116]. In addition, several terpenoids that we identified in the IVL DCM fraction are known to induce apoptosis [95][96][97][98][99][100][101][102][103][104][105][106]. For instance, caryophyllene oxide has been shown to induce apoptosis of A549 cells [100] and has been reported to induce apoptosis through the PI3K/AKT/mTOR/S6K1 pathway [102]. ...
Inula viscosa is a widely used plant in traditional Mediterranean and Middle Eastern medicine for various illnesses. I. viscosa has been shown to have anticancerous effects against various cancers, but its effects against lung cancer have been under limited investigation. At the same time, I. viscosa is rich in terpenoids whose anti-lung cancer effects have been poorly investigated. This study aimed to examine the potential anticancerous properties of methanolic and aqueous extracts of stems and leaves of I. viscosa and its terpenoid-rich fraction against human lung cancer A549 cells. Results showed a high radical scavenging capacity and polyphenol and flavonoid contents of I. viscosa methanolic rather than aqueous extracts. In addition, leaves methanolic extracts (IVLM) showed the highest reduction in viability of A549 cells among all the extracts. IVLM also reduced the viability of human ovarian SK-OV-3, breast MCF-7, liver HepG2, and colorectal HCT116 cancer cells. A terpenoid-rich I. viscosa fraction (IVL DCM), prepared by liquid-liquid separation of IVLM in dichloromethane (DCM), displayed a substantial reduction in the viability of A549 cells (IC50= 27.8 ± 1.5 µg/mL at 48 h) and the panel of tested cancerous cell lines but was not cytotoxic to normal human embryonic fibroblasts (HDFn). The assessment of IVL DCM phytochemical constituents using GC-MS analysis revealed 21 metabolites, highlighting an enrichment in terpenoids, such as lupeol and its derivatives, caryophyllene oxide, betulin, and isopulegol, known to exhibit proapoptotic, and antimetastatic functions. IVL DCM also showed robust antioxidant capacity and decent polyphenol and flavonoid contents. Furthermore, Western blotting analysis indicated that IVL DCM reduced proliferation (reduction of proliferation marker Ki67 and induction of proliferation inhibitor proteins P21 and P27), contaminant with P38 MAP kinase activation, and induced the intrinsic apoptotic pathway (P53/BCL2/BAX/ Caspase3/PARP) in A549 cells. IVL DCM also reduced the migration of A549 cells, potentially by reducing FAK activation. Future identification of anticancer metabolites of IVL DCM, especially terpenoids, is recommended. These data place I. viscosa as a new resource of herbal anticancer agents.
... Salvia species LNCaP Inhibition of cell growth [76] α-pinene Rosemary, lavender and others PC3 and DU145 Inhibition of cell growth, induced apoptosis and cell cycle arrest [77] β-Caryophyllene oxide Cinnamon, oregano, clove and black pepper PC3 Inhibition of cell growth; induced apoptosis by inhibiting PI3K/AKT/mTOR/S6K1 signaling; reduced mitochondrial membrane potential; cytochrome c release; activating caspase-3; cleavage of PARP; ROS generation; downregulation of Bcl-2, Bcl-xL, survivin, IAP-1, IAP-2 and cyclin D1; upregulation of p53 and p21; and downregulation of COX-2 and VEGF [78,79] DU145 Inhibition of cell growth and invasion and constitutive STAT3 activation [80] β-elemene Curcuma and Cymbopogon species PC3 and DU145 Inhibition of cell growth; induced apoptosis through cleaved caspase-3, caspase-9 and increasing PARP levels; and downregulated and Bcl-2 [81] Carvacrol Thyme, oregano and others DU145 Inhibition of cell growth, induction of apoptosis, cell cycle arrest increased caspase-3 activation and ROS generation [82] PC3 Inhibition of cell growth; migration and invasion; induction of apoptosis increased caspase activation and ROS generation; disruption of mitochondrial membrane potential; cell cycle arrest; upregulation of Bax and downregulation of Bcl-2 expression; decreased expression of Notch1, Jagged-1, cyclin D1 and CDK4; and increased expression of p21 [83] PC3 and DU145 ...
... The sesquiterpene has also induced apoptosis by inhibiting PI3K/AKT/mTOR/S6K1 signaling, which reduced mitochondrial membrane potential and cytochrome c release, activating caspase-3, the cleavage of PARP, ROS generation, the downregulation of antiapoptotic proteins (Bcl-2, Bcl-xL, survivin, IAP-1 and IAP-2), cell cycle protein cyclin D1 and the upregulation of the tumor suppressor protein p53 and CDK inhibitor p21. In addition, β-Caryophyllene oxide downregulated proteins linked with metastasis and angiogenesis (COX-2 and VEGF) [78,79]. Another report showed that β-Caryophyllene oxide inhibited the cell growth, invasion and constitutive STAT3 activation in DU145 cells. ...
Since prostate cancer (PCa) relies on limited therapies, more effective alternatives are required. Essential oils (EOs) and their bioactive compounds are natural products that have many properties including anticancer activity. This review covers studies published between 2000 and 2023 and discusses the anti-prostate cancer mechanisms of the EOs from several plant species and their main bioactive compounds. It also provides a critical perspective regarding the challenges to be overcome until they reach the market. EOs from chamomile, cinnamon, Citrus species, turmeric, Cymbopogon species, ginger, lavender, Mentha species, rosemary, Salvia species, thyme and other species have been tested in different PCa cell lines and have shown excellent results, including the inhibition of cell growth and migration, the induction of apoptosis, modulation in the expression of apoptotic and anti-apoptotic genes and the suppression of angiogenesis. The most challenging aspects of EOs, which limit their clinical uses, are their highly lipophilic nature, physicochemical instability, photosensitivity, high volatility and composition variability. The processing of EO-based products in the pharmaceutical field may be an interesting alternative to circumvent EOs’ limitations, resulting in several benefits in their further clinical use. Identifying their bioactive compounds, therapeutic effects and chemical structures could open new perspectives for innovative developments in the field. Moreover, this could be helpful in obtaining versatile chemical synthesis routes and/or biotechnological drug production strategies, providing an accurate, safe and sustainable source of these bioactive compounds, while looking at their use as gold-standard therapy in the close future.
... However, there is evidence that this compound targets PI3K. The results of Park et al. showed that CPO causes apoptosis by increasing mitochondrial ROS production in addition to inhibiting the constitutive activation of the PI3K/AKT/mTOR/S6K1 signaling pathway in PC-3 human prostate and MCF-7 breast cancer cells [54]. The inhibition activity of CPO may be closely related to its showcased binding pattern, which is similar to that of other PI3Kα inhibitors. ...
This study aims to assess the potential anticancer activity of lemongrass essential oil (LEO) using in vitro and in silico methods. The steam hydrodistillation of the aerial parts yielded 3.2% (wt) LEO. The GC-MS analysis of the LEO revealed the presence of α-citral (37.44%), β-citral (36.06%), linalool acetate (9.82%), and d-limonene (7.05%) as major components, accompanied by several other minor compounds. The antioxidant activity, assessed using the DPPH assay, revealed that LEO exhibits an IC50 value of 92.30 μg/mL. The cytotoxic effect of LEO, as well as LEO solubilized with Tween-20 (LEO-Tw) and PEG-400 (LEO-PEG), against a series of cancer cell lines (A375, RPMI-7951, MCF-7, and HT-29) was assessed using the Alamar Blue assay; the results revealed a high cytotoxic effect against all cell lines used in this study. Moreover, neither one of the tested concentrations of LEO, LEO-PG, or LEO-TW significantly affected the viability of healthy HaCaT cells, thus showing promising selectivity characteristics. Furthermore, LEO, LEO-PG, and LEO-TW increased ROS production and decreased the mitochondrial membrane potential (MMP) in all cancer cell lines. Moreover, LEO treatment decreased all mitochondrial respiratory rates, thus suggesting its ability to induce impairment of mitochondrial function. Molecular docking studies revealed that LEO anticancer activity, among other mechanisms, could be attributed to PDK1 and PI3Kα, where the major contributors are among the minor components of the essential oil. The highest active theoretical inhibitor against both proteins was β-caryophyllene oxide.
... The incidence of chemotherapy-induced POF ranges from 70 to 100% [3] . Cyclophosphamide (CTX), a chemotherapeutic agent, remains one of the most successful and widely used antitumor agents [4] . As an alkylating agent, CTX induces non-cyclical toxic effects on cells. ...
Background Premature ovarian failure (POF) is a clinical condition characterized by a diminished ovarian reserve occurring before the age of 40, significantly affecting female reproductive health. However, its exact pathogenesis remains unclear. This research aimed to examine the mechanisms of cyclophosphamide (CTX)-induced senescence and apoptosis in the ovarian and cerebral cortex tissues of rats to provide insights into delaying aging and protecting female reproductive health. Methods A POF rat model was established via intraperitoneal injection of CTX, with the modeling effect confirmed by measuring ovarian volume and weight. Serum changes were detected using enzyme-linked immunosorbent assay (ELISA). Senescence-associated β-galactosidase (SA-β-gal) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining were performed to assess brain cortex and ovarian tissues. Western blotting and quantitative polymerase chain reaction (RT-qPCR) were used to detect the expression levels of proteins and genes related to cellular senescence and apoptosis, validating the correlation between POF, cellular senescence, and apoptosis. Results High-dose CTX induced POF. In rats with POF, the levels of anti-Müllerian hormone (AMH), estradiol (E2), and vitamin D (VD) significantly decreased ( P < 0.0001 ), whereas the levels of testosterone (T) and insulin (INS) significantly increased ( P < 0.0001 ). The number of senescent and apoptotic-positive cells in the ovarian and cerebral cortex tissues of rats with POF was substantially augmented ( P < 0.05; P < 0.01 ). Additionally, the expression of senescence-related proteins cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (P53), apoptosis-related protein BCL2-Associated X Protein (Bax), and cysteine-aspartic acid protease 3 (caspase 3) was upregulated. In contrast, the expression of the anti-apoptotic protein BCL-2 was downregulated. These findings demonstrated that high-dose CTX injection leads to cellular senescence and apoptosis, resulting in ovarian pathology. Conclusion High-dose CTX induced POF in rats, resulting in aging and apoptosis in the cerebral cortex and ovarian tissues. Therefore, inhibiting cellular senescence and apoptosis may be a potential approach for restoring ovarian reserve function in POF.
... µg/mL [28]. In terms of structure, caryophyllene oxide was shown to have more potential due to possessing an epoxide exocyclic functionality, making the compound bind covalently to DNA bases and proteins to initiate signalling in cancer cells [29]. Caryophyllene and caryophyllene oxide could also potentiate the efficacy of anticancer drugs, such as doxorubicin [30] and paclitaxel [31], by increasing the drug concentrations inside the cancer cells. ...
Hedychium coronarium, commonly known as white ginger lily (Zingiberaceae), is a native species in Asian forests. The plant has long been used as a traditional medicine for treating pain and inflammatory conditions and as a food-flavouring spice. In this work, the essential oil samples prepared from Hedychium coronarium leaves, rhizomes, and stems were analyzed by gas chromatography coupled with the mass spectrometry (GC/MS) method, which gave information on the main chemical components of leaf essential oil [β-pinene (27.90%), caryophyllene (23.93%), caryophyllene oxide (17.31%)], rhizome essential oil [β-pinene (29.56%), sabinene (12.05%), coronarin E (10.91%), p-cymene (10.39%), and α- pinene (10.06%)], and stem essential oil [α-phellandrene (18.71%), p-cymene (12.68%), β-pinene (12.18%)]. Three essential oils were also evaluated for their cytotoxic effects against SK-LU-1 cells (lung adenocarcinoma). The leaf essential oil was shown to be the most potent cytotoxic agent with an IC50 value of 80.19 ± 3.32 μg/mL. The cytotoxic activity against SK-LU-1 cells of the essential oils of Hedychium coronarium was reported for the first time. The results of this investigation indicated the similarities and differences among the chemical compositions of leaf, rhizome, and stem parts of Hedychium coronarium collected in Vietnam, which can be considered a potential and inexpensive resource of zingiberaceous essential oils. Keywords: Hedychium coronarium; essential oil; GC/MS; SK-LU-1
... Apart from their direct anticancer properties, terpenes have been observed to enhance the effectiveness of traditional chemotherapy in preclinical studies. For instance, β-caryophyllene (a terpene from essential oils) heightens the sensitivity of melanoma cells to doxorubicin by blocking the drug efflux pump responsible for drug resistance (Park et al., 2011). ...
Cancer, a persistent challenge to global health, is one of the prominent contributors of morbidity and mortality, regardless of the degree of human development. Numerous conventional treatment approaches including chemotherapy, surgery, radiotherapy, immunotherapy, and hormonal therapies have significant limitations, and patients face unfavorable outcomes. Therefore, these treatment approaches necessitate a continuous exploration of novel treatment modalities to minimize the existing limitations including the side effects and toxicities of treatment modalities. In this regard, phytochemicals are getting significant interest because of their capacity to target numerous molecular pathways involved in cancer development without any toxicity. Dietary antioxidant phytochemicals are present in abundance in plants representing different classes of compounds, which exhibit various mechanisms of actions on all stages of tumors. Several preclinical studies reported a significant role of phytochemicals in cancer prevention, whether obtained through a regular diet abundant in fruits and vegetables or via supplements designed to provide the necessary daily dose of active phytochemicals. This book chapter covers an in-depth analysis of preclinical and clinical studies of phytochemicals in cancer treatment, major preclinical findings, clinical trial outcomes, and the potential integration of these phytochemicals into mainstream oncology practices.
... ROS can induce apoptotic cell death by promoting the loss of mitochondrial membrane potential with subsequent activation of the caspase-dependent apoptotic pathway [4][5][6]. Accordingly, numerous studies have illustrated that some anticancer compounds of natural origin can induce apoptosis in cancer cells via ROS generation [5,[7][8][9][10]. Medicinal plants have been of interest for centuries in cancer treatment, mainly because many currently used drugs with anticancer activity have been obtained from natural resources. ...
Background
The leaves of Kalanchoe pinnata (Lam.) Pers. (K. pinnata), a succulent plant native to tropical regions, are used as a medicinal alternative against cancer in several countries worldwide; however, its therapeutic potential to fight cancer has been little addressed. In this study, we analyzed the phytochemical content, antioxidant capacity, and selectivity of K. pinnata leaf ethanolic extract against different human cancer cell lines in vitro.
Methodology
This study subjected the ethanolic extract to enzymatic assays to quantify the phytochemical content (phenolics, flavonoids, and anthraquinones) and its radical scavenging and iron-reducing capacities. Also, the phytoconstituents and major phenolic compounds present in the extract’s subfractions were identified by GC-MS, HPLC, and NMR. Human cancer (MCF-7, PC-3, HT-29) and normal colon (CoN) cell lines were treated with different concentrations of K. pinnata leaf ethanolic extract, and the changes in cell proliferation (sulforhodamine B assay), caspases activity (FITC-VAD-FMK reporter), mitochondrial membrane potential (MMP, rhodamine 123 assay), chromatin condensation/fragmentation (Hoechst 33342 stain), and ROS generation (DCFH2 probe assay) were assessed.
Results
The results showed that the K. pinnata leaf ethanolic extract is rich in phytoconstituents with therapeutic potential, including phenols (quercetin and kaempferol), flavonoids, fatty acid esters (34.6% of the total composition), 1- triacontanol and sterols (ergosterol and stigmasterol, 15.4% of the total composition); however, it presents a poor content of antioxidant molecules (IC50 = 27.6 mg/mL for H2O2 scavenging activity vs. 2.86 mg/mL in the case of Trolox). Notably, the extract inhibited cell proliferation and reduced MMP in all human cell lines tested but showed selectivity for HT-29 colon cancer cells compared to CoN normal cells (SI = 8.4). Furthermore, ROS generation, caspase activity, and chromatin condensation/fragmentation were augmented significantly in cancer-derived cell lines, indicating a selective cytotoxic effect.
Conclusion
These findings reveal that the K. pinnata leaf ethanolic extract contains several bioactive molecules with therapeutic potential, capable of displaying selective cytotoxicity in different human cancer cell lines.
... Once Ras protein binds to GTP, it becomes activated, recruits Raf to the cell membrane, and subsequently activates the MAPK pathway through phosphorylation of MAPK (Meng et al. 2018). The MAPK signaling pathway can be activated by reactive oxygen species and numerous inflammatory factors, further promoting the production of other inflammatory factors (Park et al. 2011). Inhibitors of MAPK have been shown to effectively alleviate inflammation and neuropathic pain in animal models (Mahurkar-Joshi et al. 2021). ...
This study is aimed at exploring the potential mechanisms of melatonin (MT) in treating chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using network pharmacology and experimental study. The target genes of MT were acquired from the Swiss Target Prediction, SuperPred, SEA, and PharmMapper databases, and the CP/CPPS targets were collected based on OMIM, DisGeNET, and GeneCards databases. The intersection of MT and CP/CPPS target genes was analyzed. A PPI network was constructed using Cytoscape to identify core targets. The shared targets underwent GO and KEGG enrichment analyses by Using R software. Molecular docking of MT with core targets was performed using AutoDock and PyMOL. GROMACS software was used for molecular dynamics simulation. And using cell experiments to verify the potential effect of MT in CP/CPPS. Network pharmacology analysis reveals 284 shared targets between MT and CP/CPPS, with AKT1, SRC, HSP90AA1, PTGS2, BCL2L1, ALB, CASP3, NFKB1, HIF1A, and ESR1 identified as key targets. Enrichment analysis indicates that MT affects CP/CPPS through various biological processes, and pathway analysis emphasizes the significance of PI3K-Akt, MAPK, Ras, FoxO, HIF-1, EGFR, and apoptosis pathways. Molecular docking confirms strong binding between MT and core targets. It is worth noting that the molecular dynamics simulation showed that the average binding free energy of AKT1, PTGS2, ALB, HSP90AA1 proteins, and MT was − 26.15, − 29.48, − 18.59, and − 20.09 kcal/mol, respectively. These results indicated that AKT1, PTGS2, ALB, and HSP90AA1 proteins were strongly bound to MT. Cell experiments demonstrate that MT can inhibit the secretion of IL-1β, IL-6, and TNF-α in LPS-induced RWPE-1 cells, alleviate inflammation, and suppress cell apoptosis and oxidative stress. Network pharmacology, molecular docking, molecular dynamics simulation, and cell experiments showed that MT could play a role in CP/CPPS by regulating multiple targets and pathways. These findings provide an important scientific basis for further exploration of the molecular mechanism and clinical application of MT in CP/CPPS treatment and are expected to provide new ideas and directions for the development of novel therapeutic strategies.
... Eugenol exerts its apoptosis-inducing effects by cleaving caspase 3, with a significant increase in its active form showing apoptosis-inducing properties (Fathy et al. 2019), which also limits the cells' ability to metastasize and proliferate in the rise in ROS and cytochrome C's release (Abdullah et al. 2018;Anwar et al. 2022). Beta-caryophyllene also induces apoptosis in mouse blood cancer cell lines through caspase 3 induction (Amiel et al. 2012) and by downregulating PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation (Park et al. 2011;Dahham et al. 2015). All these four hub proteins (HSP90AA1, IGF-1R, ESR1, and CASP3) affect other proteins in downstream mechanisms in a way that inhibits cancer cell proliferation, induces apoptosis, and thus provides anticancer and anti-metastatic properties. ...
This study explores the potential of essential oils, Eugenol (EUG), and Beta-Caryophyllene (BCP) in enhancing the efficacy of the chemotherapeutic drug 5-fluorouracil (5-FU) in treating metastatic colorectal cancer (CRC). Pharmacokinetic assessment through ADMET analysis indicates that EUG and BCP adhere to the rule of five with good bioavailability, ensuring their drug-likeness properties. The study employs a multitarget strategy to reduce drug dosage and enhance effectiveness, testing the compounds on the HCT116 human colorectal cancer cell line. MTT assay revealed in-vitro cytotoxic effects of EUG, BCP, and 5-FU, with a noteworthy reduction in IC50 values observed when combining the compounds, indicating synergistic effects (CI < 1) as depicted in the Fa-CI plot. Network pharmacology-based analysis of the compound-disease-target (C-D-T) network identifies 58, 24, and 49 target proteins for EUG, BCP, and 5-FU, respectively, in metastatic CRC. Venn diagram intersection reveals 11 common target proteins, and the merged C-D-T network highlights 84 target proteins, with 16 selected based on edge count, including HSP90AA1, IGF-1R, ESR1, and CASP3. Molecular docking studies indicate that EUG, BCP, and 5-FU effectively inhibit the core target protein HSP90AA1 within the C-D-T network, suggesting their potential as modulators for CRC metastasis. These findings propose a promising approach for developing drugs targeting specific proteins to mitigate metastasis in colorectal cancer.
... For this reason, BCPO reveals a high potential to be a signaling modulator in cancerous tumor cells. The anticancer activities of both sesquiterpenes can be exerted by suppressing cell growth and inducing apoptosis [51]. The 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C28 modified derivative methyl-ester (CDDO-Me, also known as bardoxolone methyl) are two synthetic derivatives of oleanolic acid (natural triterpene). ...
Cancer is a disease that encompasses multiple and different malignant conditions and is among the leading causes of death in the world. Therefore, the search for new pharmacotherapeutic options and potential candidates that can be used as treatments or adjuvants to control this disease is urgent. Natural products, especially those obtained from plants, have played an important role as a source of specialized metabolites with recognized pharmacological properties against cancer, therefore, they are an excellent alternative to be used. The objective of this research was to evaluate the action of the monoterpene isoespintanol (ISO) against the human tumor cell lines MDA-MB-231, A549, DU145, A2780, A2780-cis and the non-tumor line MRC-5. Experiments with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and fluorescence with propidium iodide (PI), 4′,6-diamidino-2-phenylindole dilactate (DAPI) and green plasma revealed the cytotoxicity of ISO against these cells; furthermore, morphological and chromogenic studies revealed the action of ISO on cell morphology and the inhibitory capacity on reproductive viability to form colonies in MDA-MB-231 cells. Likewise, 3D experiments validated the damage in these cells caused by this monoterpene. These results serve as a basis for progress in studies of the mechanisms of action of these compounds and the development of derivatives or synthetic analogues with a better antitumor profile.
... In addition, in different tumor cells, β-caryophyllene oxide (68) can simultaneously target PI3K/AKT/mTOR/S6K1 and MAPK signaling pathways, inhibit the proliferation of related tumor cells and induce the apoptosis of tumor cells by activating caspase-3 and releasing cytochrome c. These results suggest that β-caryophyllene oxide (68) is a potential candidate drug for the prevention and treatment of cancer [138][139][140]. ...
Artabotrys, a pivotal genus within the Annonaceae family, is renowned for its extensive biological significance and medicinal potential. The genus’s sesquiterpene compounds have attracted considerable interest from the scientific community due to their structural complexity and diverse biological activities. These compounds exhibit a range of biological activities, including antimalarial, antibacterial, anti-inflammatory analgesic, and anti-tumor properties, positioning them as promising candidates for medical applications. This review aims to summarize the current knowledge on the variety, species, and structural characteristics of sesquiterpene compounds isolated from Artabotrys plants. Furthermore, it delves into their pharmacological activities and underlying mechanisms, offering a comprehensive foundation for future research.
... For this reason, BCPO reveals a high potential to be a signaling modulator in cancerous tumor cells. The anticancer activities of both sesquiterpenes can be exerted by suppressing cell growth and inducing apoptosis [50]. 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), and its C28 modified derivative methyl-ester (CDDO-Me, also known as bardoxolone methyl), are two synthetic derivatives of oleanolic acid (natural triterpene). ...
Cancer is a disease that encompasses multiple and different malignant conditions and is among the leading causes of death in the world. Therefore, the search for new pharmacotherapeutic options and potential candidates that can be used as treatments or adjuvants to control this disease is urgent. Natural products, especially those obtained from plants, have played an important role as a source of specialized metabolites with recognized pharmacological properties against cancer, therefore, they are an excellent alternative to be used. The objective of this research was to evaluate the action of the monoterpene isoespintanol (ISO) against the human tumor cell lines MDA-MB-231, A549, DU145, A2780, A2780-cis and the non-tumor line MRC-5. Experiments with MTT and fluorescence with propidium iodide (PI), DAPI and green plasma revealed the cytotoxicity of ISO against these cells; furthermore, morphological and chromogenic studies revealed the action of ISO on cell morphology and the inhibitory capacity on reproductive viability to form colonies in MDA-MB-231 cells. Likewise, 3D experiments validated the damage in these cells caused by this monoterpene. These results serve as a basis for progress in studies of the mechanisms of action of these compounds and the development of derivatives or synthetic analogues with a better antitumor profile.
... The Ras signaling pathway is pivotal in various physiological processes, including cell proliferation, migration, and apoptosis. Once Ras protein binds to GTP, it becomes activated, recruits Raf to the cell membrane, and subsequently activates the MAPK pathway through phosphorylation of MAPK [31].The MAPK signaling pathway can be activated by reactive oxygen species and numerous in ammatory factors, further promoting the production of other in ammatory factors [32].Inhibitors of MAPK have been shown to effectively alleviate in ammation and neuropathic pain in animal models [33]. ...
Objective: This study aims to explore the potential mechanisms of melatonin (MT) in treating chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using network pharmacology and molecular docking.
Methods: The target genes of MT were acquired from the Swiss Target Prediction, Superpred, SEA, and PharmMapper databases and the CP/CPPS targets were collected based on OMIM, Disgenet, and Genecards databases. The intersection of MT and CP/CPPS target genes was analyzed. A PPI network was constructed using Cytoscape to identify core targets. The shared targets underwent GO and KEGG enrichment analyses by Using R software. Molecular docking of MT with core targets was performed using AutoDock and PyMol. And using cell experiments to verify the potential effect of MT in CP/CPPS.
Results: Network pharmacology analysis reveals 284 shared targets between MT and CP/CPPS, with AKT1, SRC, HSP90AA1, PTGS2, BCL2L1, ALB, CASP3, NFKB1, HIF1A, and ESR1 identified as key targets. Enrichment analysis indicates that MT affects CP/CPPS through various biological processes, and pathway analysis emphasizes the significance of PI3K-Akt, MAPK, Ras, FoxO, HIF-1, EGFR, and apoptosis pathways. Molecular docking confirms strong binding between MT and core targets. Cell experiments demonstrate that MT can inhibit the secretion of IL-1β, IL-6, and TNF-α in LPS induced RWPE-1 cells, alleviate inflammation, and suppress cell apoptosis and oxidative stress.
Conclusion: Network pharmacology, molecular docking and cell experiments showed that MT could play a role in CP/CPPS by regulating multiple targets and pathways. This provides valuable insights for a more in-depth investigation into the molecular mechanisms and clinical applications of MT in CP/CPPS treatment.
... Eubacterium_coprostanoligenes_group, Oscillospiraceae-UCG_005, Oscillospiraceae-UCG_002, and Eubacterium_ruminantium_group were all negatively correlated with (-)-caryophyllene oxide and glycerophospho-N-palmitoyl ethanolamine, and positively correlated with 1-(4-methyl-2morpholino-1,3-thiazol-5-yl) ethan-1-one. The abundance of (-)-caryophyllene oxide and glycerophospho-N-palmitoyl ethanolamine, which have been identified as metabolites with potential benefits in anti-inflammatory responses, was decreased in FC patients (Park et al., 2011;Li et al., 2021;Su et al., 2022). Conversely, the concentration of 1-(4-methyl-2-morpholino-1,3thiazol-5-yl) ethan-1-one was observed to be elevated in the FC group. ...
Introduction
Gut microbiota and metabolites have been identified to contribute to the pathogenesis of functional constipation (FC); however, the underlying mechanism(s) have not been elucidated, and the relationship between the gut microbiota and metabolites in FC has received limited attention in the literature.
Methods
16S rDNA sequencing and non-targeted metabolomic detection based on liquid chromatography-mass spectrometry (LC–MS/MS) technologies were combined to analyze the altered gut microbiome and metabolic profile of fecal samples from FC patients and healthy individuals (healthy control; HC).
Results
The richness and diversity of gut microbiota significantly (p < 0.01) increased in FC patients. Compared to the HC group, 18 genera, including Intestinibacter, Klebsiella, and Akkermansia, exhibited statistically significant changes (p < 0.05). Metabolic analysis showed that metabolic profiles were also markedly altered with 79 metabolites, such as (-)-caryophyllene oxide, chenodeoxycholic acid, and biliverdin, indicating significant inter-group differences (p < 0.05). Besides, the primary bile acid biosynthesis, as well as the metabolic profile of porphyrin and chlorophyll, were the most dominant enriched pathways (FDR < 0.01), in which chenodeoxycholic acid and biliverdin were significantly enriched, respectively. Correlation analysis demonstrated a strong relationship between 10 genera and 19 metabolites (r > 0.6, FDR < 0.05), and notably, Intestinibacter showed a negative correlation with biliverdin (FDR < 0.001), which highlighted the interplay of the gut microbiota and metabolites in the pathogenesis of FC.
Conclusion
Our research describes the characteristics of the gut microbiota and metabolic profiles and the correlation between the gut microbiota and metabolites in FC patients. This may contribute to the understanding of the underlying mechanisms involved in FC pathogenesis and may provide novel insights into therapeutic interventions.
... Cyclosativene has been reported to possess anticancer properties and can serve as a potential antitumor agent (Lin et al., 2012;Turkez et al., 2015). Furthermore, pentacosane (Mishra et al., 2019), α-copaene (Turkez et al., 2014), caryophyllene oxide (Fidyt et al., 2016;Pan et al., 2016;Park et al., 2011;Shabana et al., 2023), 1-docosene (Sneha and Varsha, 2018;Swantara et al., 2019) have been demonstrated to have antitumor activity. Therefore, the significant anticancer activity of P. puberula root PEE against A549 may be due to the important role played by these major chemical components. ...
... However, in Bulgarian EO, its concentration is even lower, 0.23%. Caryophylene oxide belongs to the group of oxygenated sesquiterpenes and exhibits a diverse spectrum of pharmacological efects, including antibacterial, antifungal, anti-infammatory, and antioxidant properties, it is considered as a therapeutic candidate for the prevention and treatment of cancer as well [49][50][51]. Bulgarian EO contains minimal amounts of β-caryophyllene, which is one of the major compounds found in Turkish species, where the concentration fuctuates around 15% [22]. ...
Stachys germanica L. (Lamiaceae) is a plant associated with a rich history in the traditional medicine of Iran, Turkey, and Serbia. However, researchers have not fully investigated the pharmacological potential of the herb, and scientifc data on this plant species are limited. Te aim of the current study was to evaluate the chemical composition of the essential oil (EO) obtained from the aerial parts of S. germanica L. growing wild in Bulgaria and to perform a comparative analysis of the chemical composition of EOs obtained from the same plant species from other geographical regions. For the evaluation of the chemical profle of the isolated EO, gas chromatographic analysis with mass spectrometry was performed. Te most abundant terpene class was oxygenated monoterpenes, which accounted for 59.30% of the total EO composition. Te bicyclic monoterpene camphor, as a compound of this class, was identifed as the major constituent in the EO, accounting for 52.96% of the total oil composition. Te chemical profle of Bulgarian EO is quite diferent compared to that of EOs from other regions. It is the only one to contain more than 50% camphor. In addition, EO contains signifcant amounts of the diterpene geranyl p-cymene (10.49%). Tis is the frst study describing the chemical composition of EO from Bulgarian Stachys germanica L., and our results reveal some future perspectives for the evaluation of the biological activity of EO from the studied plant species as a new therapeutic agent or natural remedy targeting diferent medical conditions. Te EO has a promising potential to be used as a biopesticide and repellent as well, an environmentally friendly and safer alternative to standard pesticides.
... The previous study shows that caryophyllene decreases following gene expression, which is responsible for cell proliferation, survival, metastasis, and angiogenesis: cyclin D1, bcl-2, bcl-xL, COX-2, VEGF, and IAP. Caryophyllene also inhibits the activation of PI3K/AKT/mTOR/S6K1 signaling cascade while increasing the activation of ERK, JNK, and p38 MAPKn in many tumor cells (Park et al., 2011). The apoptosis mechanism of ovarian cancer cells following caryophyllene treatment is mediated by caspase-3 activation and PARP cleavage (Arul et al., 2020). ...
Thyme contains phytochemicals that exhibit cytotoxic and cytogenic activities. Differ solvents have different abilities in dissolving plant bioactive compounds. The objective of this study is to determine the anticancer properties of thyme leaves and twigs including profile of bioactive compounds, cytotoxicity, ability of apoptosis induction and caspase-3 activation of different solvent extracts on T47D breast cancer cell line. An experimental study was conducted in eight groups. T47D breast cancer cell line was treated with thyme extracts as treatment group, doxorubicin as positive control, while untreated T47D cells were used as negative control. Thyme was extracted by maceration using 6 different solvents: methanol, ethanol, chloroform, ethyl acetate, dichloromethane, and n-hexane. Bioactive compounds of all extracts were analyzed by GC-MS. Cytotoxicity was investigated through MTT assay on T47D breast cancer cell line. The percentage of apoptosis and caspase-3 were detected by flow cytometry using Annexin V-PI and BD Cytofix/Cytoperm, respectively. Thymol as the main bioactive compound in thyme was found in all extracts. MTT results revealed that six solvents extracts had moderate to weak cytotoxicity with dichloromethane had the lowest IC50 values at 120.23 µg/ml. All thyme extracts promoted apoptosis in T47D cells with apoptosis percentage of methanol, chloroform, ethyl acetate, ethanol, dichlorometane, n-Hexane and doxorubicin were 82.67; 80.98; 73.13; 72.28; 60.62; 27.74 and 98.43%, respectively. Among all extracts, methanol extract showed the highest apoptosis and caspase-3 activation percentage. We conclude that all thyme extracts had anticancer properties in T47D breast cancer cell line although efficacy of each solvent extract was differed.
... Caryophyllene oxide (Fig 2) is the major compound present in the essential oil of rhizomes of Cyperus luzulae from this study. Literature reported caryophyllene oxide affects the growth of tumor cells, and may be used against cancer of the prostate, human breast, cancer cells of human osteosarcoma MG-63, lung cancer cells, and gastric cancer cells [24][25][26][27][28][29], which makes C. luzulae essential oil interesting for future studies against cancer cells. ...
Cyperus luzulae (L.) Rottb. ex Retz is an understudied species within the Cyperus genus. To the best of the authors’ knowledge, the essential oil from this species has never been fully characterized. Essential oil obtained through steam distillation of C. luzulae rhizomes was analyzed to establish the chemical profile by GC/FID and GC/MS. The chemical profile revealed a high content of sesquiterpene hydrocarbons (36.9%) and oxygenated sesquiterpenes (34.9%). The major compounds of the oil were caryophyllene oxide(23.5%), β-selinene (12.9%), and α-copaene (8.3%). These results provide fundamental data for future investigations into the ethnobotanical and pharmacological uses of this species, broadening the scope of knowledge on the Cyperus genus and its potential applications.
... It was discovered that β-caryophyllene oxide not only inhibited the constitutive activation of the PI3K/AKT/ mTOR/S6K1 signaling cascade in tumor cells but also activated numerous protein kinases, including ERK, JNK, and p38 MAPK, and increased the production of reactive oxygen species from mitochondria, linking it to apoptosis (Ahmed et al., 2022;Park et al., 2011). Meanwhile, α-pinene reduced the invasiveness of highly metastatic human breast cancer cells by inhibiting induced tumor necrosis factor (TNF); TNF is a primary cytokine involved in regulating systemic inflammation and is produced by a variety of cells, including macrophages, lymphocytes TNF is one of the primary cytokines involved in regulating systemic inflammation and is produced by a variety of cells, including macrophages, lymphocytes, and others (Kang et al., 2016). ...
Objective:
Alpinia elegans (Zingiberaceae) is a Philippine endemic plant reported to have various folkloric uses. The seed oil of A. elegans has been shown to contain a majority of the following bioactive compounds: D-limonene, α-pinene, and caryophyllene oxide. The study sought to determine if the bioactive compounds found in A. elegans seed oil would be a good natural, inexpensive, and less-detrimental alternative for cancer treatment.
Methods:
The study utilized in silico (Way2Drug predictive services, SwissADME, AutoDock 4) experiment to examine the aforementioned compounds as viable therapeutic candidates against human cancer cell lines.
Result:
Results determined that the compounds D-limonene, α-pinene, and caryophyllene oxide were most potent against thyroid gland carcinoma (8505C) cells, brain glaucoma (Hs 683) cells, and promyeloblast leukemia (HL-60) cells, respectively. Additionally, D-limonene was the only compound to show arrhythmia as an adverse effect. Predictions showed that the compounds could inhibit cellular growth factors and serine/threonine-protein kinase activity. The compounds generated a bioavailability score of 0.55 and exhibited blood-brain barrier (BBB) penetration. D-limonene, α-pinene, and caryophyllene oxide had binding energy of -4.59, -5.43, and -6.92, respectively.
Conclusion:
The binding energy indicated that the ligands could securely dock to the receptors, thus suggesting that interaction between the ligands and receptors was stable. Results have shown that the compounds are promising candidates against human cancer cell lines by inhibiting cell proliferation and inducing apoptosis.
... Several critical intermediates in this pathway are highly susceptible to redox dysregulation. ROS can oxidize the cysteine moieties of various phosphatases (PTEN, PTP), leading to their inactivation, which, in turn, facilitates the growth and survival of tumor cells [34]. The transcription factor NF-κB is also affected by ROS, where ROS can influence the activity of IKK upstream of NF-κB. ...
The reversible oxidation-reduction homeostasis mechanism functions as a specific signal transduction system, eliciting related physiological responses. Disruptions to redox homeostasis can have negative consequences, including the potential for cancer development and progression, which are closely linked to a series of redox processes, such as adjustment of reactive oxygen species (ROS) levels and species, changes in antioxidant capacity, and differential effects of ROS on downstream cell fate and immune capacity. The tumor microenvironment (TME) exhibits a complex interplay between immunity and regulatory cell death, especially autophagy and apoptosis, which is crucially regulated by ROS. The present study aims to investigate the mechanism by which multi-source ROS affects apoptosis, autophagy, and the anti-tumor immune response in the TME and the mutual crosstalk between these three processes. Given the intricate role of ROS in controlling cell fate and immunity, we will further examine the relationship between traditional cancer therapy and ROS. It is worth noting that we will discuss some potential ROS-related treatment options for further future studies.
Background
β-Caryophyllene oxide (BCPO) has wooden odor so widely used as cosmetic and food additives. It is naturally found in various spice and food plant such as basil, black pepper, clove, salvia, and indian bay leaf. It is traditionally used to treat arthritis. The present study anticipated to appraise the anti-inflammatory and anti-arthritic potential of BCPO alone and in combination with methotrexate.
Results
Data from in vitro assays showed that BCPO exerted the highest percentage inhibition at 1600 μg/ml. Complete Freund’s Adjuvant-induced arthritis in Wistar rats treated with BCPO and its combination with methotrexate (MTX) revealed a notable restoration of body weight and reduced pain, arthritic score, oxidative stress, and hematological alterations in contrast to disease control. The histopathological examination showed that BCPO therapy decreased joint inflammation, pannus formation, and bone erosion. Biochemical studies revealed that BCPO alone and in combination not only downregulated the mRNA expression of TNF-α, IL-1β, NF-kB, and COX-2 but also increased the expression of IL-4, and IL-10.
Conclusion
It can be inferred from the finding that BCPO in combination with MTX can be effectively used to manage polyarthritis due to notable anti-inflammatory, antioxidant, and anti-nociceptive activities than monotherapy.
Graphical abstract
Members of the Cinnamomum genus have been utilized for medicinal treatment for millennia. In recent years, particular attention has been given to the bioactive metabolites involved in the medicinal properties of natural products and their extracts. Cinnamon is particularly interesting due to the presence of both terpenoid and polyphenol moieties, both of which have been extensively studied for their medicinal applications in the treatment of a wide range of conditions, from bacterial infection, obesity and diabetes to cancer and cardiovascular pathologies. Here, we reviewed some of the properties of cinnamon and its derivatives cinnamic acid, trans-cinnamaldehyde and beta-caryophyllene. In addition, recent advancements in the application of cinnamon and its derivatives in cancer, particularly focusing on gynecological and breast cancers, which present unique challenges to treatment due to late diagnosis, have been discussed. Current advancements to further enhance the delivery of cinnamon and its derivatives through nanoencapsulation and nanoparticulate strategies as well as the development of novel conjugates and hybrids are also discussed. Additionally, the use of cinnamon and its derivatives as adjuvants with chemotherapeutics that can work synergistically was also touched upon. Overall, biotechnological innovations have enhanced the delivery of natural products such as cinnamon and its derivatives and may pave the path for novel therapeutic strategies with fewer side effects and higher potency. Cinnamon represents a valuable source of developing novel anticancer materials that warrant additional research for development as potential interventions or combination treatments.
Terpenes are among the wide reaching and diversified collection of naturally occurring molecules. Terpenes possess broad range of therapeutic benefits. The ability of terpenes to terminate tumor growth and as a source to prompt cell apoptosis has focused over the anticancer activity of terpenes. Although terpenes act as a potential anticancer agent, nevertheless limited bioavailability is one of the main hitches that restricts the in vivo effectiveness of terpenes. In addition, some terpenes exert toxicological effects that need to confront. In this regard nanotechnology has proven to be an effective approach to pull out the bioavailability barriers with reduced toxicity by means of specific drug activity, enhanced drug permeability and high drug loading efficiency. This review addressed the potential therapeutic benefits of terpenes as anti-cancer agents, as well as the challenges that certain terpenes encountered and how nanotechnology can help to overcome them.
Globally, melanoma is the leading cause of cancer-related deaths. Melanoma is a serious and possibly lethal form of skin cancer. Standard cancer therapies, such as radiation, chemotherapy, and surgical excision, have been used to treat malignant melanoma. Unfortunately, adverse side effects and treatment resistance sometimes render these medicines unsuccessful. Consequently, there is growing interest in developing more effective and safe substitute melanoma therapies. Terpenes are a large class of naturally occurring compounds generated from plants that have drawn interest as potential anticancer medications due to their ability to induce apoptosis in cancer cells and limit the growth of tumors. The present understanding of terpenes' anticancer properties was outlined in this review, with a particular emphasis on their potential as therapeutic agents for malignant melanoma. Thymoquinone, β-elemene, carvacrol, limonene, α-pinene, β-caryophyllene, taxol, betulinic acid, α-bisabolol, ursolic acid, linalool, lupeol, and artesunate are many examples of terpenes.
Jasminum sambac, commonly known as Arabian jasmine, is a traditional medicinal plant with a broad spectrum of therapeutic properties. Recent studies have focused on its potential anticancer activities, particularly through the inhibition of the PI3K-AKT-mTOR pathway, a critical signaling cascade involved in cell growth, proliferation, survival, and metabolism. This review explores the anticancer properties of J. sambac and its bioactive phytochemicals, utilizing molecular docking and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyses to evaluate their efficacy and safety. For this, literature review data were collected as of August 6, 2024, and further molecular docking was done with the selected phytochemicals against PI3K, AKT, and mTOR (PDB ID: 5DXT, 6HHF, and 8PPZ, respectively) proteins. The results indicated that J. sambac and its bioactive compounds, particularly hesperidin (HPN) and quercetin (QRN), demonstrated significantly inhibited PI3K-AKT-mTOR pathways and showed high binding affinity against PI3K and AKT, with values of –10.5 and –10.9 kcal/mol for HPN and –8.2 and –9.5 kcal/mol for QRN, respectively. In comparison, co-crystal ligands exhibited binding energies of –8.2 and –13.5 kcal/mol. Additionally, all compounds demonstrated higher binding affinity for mTOR compared to the co-crystal ligands, with oleanolic acid (OA) exhibiting the highest affinity. The ADMET analyses suggest favorable pharmacokinetic properties and low toxicity profiles, making J. sambac phytochemicals a promising candidate for developing anticancer therapies. This review and in silico studies highlights the importance of further clinical research to validate these findings and also J. sambac and its bioactive compounds as effective as well as safe anticancer agents.
Prostate cancer is among the tumors that contribute to the increasing male mortality rate due to cancer worldwide. Treatment options for prostate cancer include active surveillance, radiation therapy, chemotherapy, hormonal therapy, focal therapy, and surgery. Ongoing research investigates alternative treatment modalities, such as traditional medicine and natural products, to address prostate cancer, drug resistance, and the side effects linked to current treatment options. Sesquiterpenes are a group of substances that are naturally made up of three isoprene units, hence fifteen carbons bound together. An extensive number of naturally occurring products—nearly 5000 in total—are categorised as secondary metabolites in the context of medicinal plants, marine organisms and fungi. Numerous of them possess many biological activities, anti-inflammatory, antioxidant, antimicrobial, and especially cytotoxic activity. Sesquiterpenes are an interesting group that was investigated due to their widespread occurrence and promising effects. Several studies have shown significant effects of sesquiterpenes on many types of cancer, including prostate cancer. Therefore, this review aims to include in vitro, in vivo and clinical studies of sesquiterpenes in prostate cancer. Based on the ring system, this review categorises sesquiterpenes as acyclic, monocyclic, bicyclic sesquiterpenes and other sesquiterpenes and their derivatives. A summary of sesquiterpenes' current status as cytotoxic with the potential for anticancer therapy agents is given concerning prostate cancer.
Graphical abstract
The world of plant diversity is endlessly fascinating and essential for life on Earth. Since the inception of early civilization, humans have utilized plants for several purposes, particularly for their medicinal value. While some plants are known for their toxicity, they also contain beneficial phytochemicals that are important for both plants and humans, indicating their dual nature. This study aims to explore and synthesize the existing knowledge on various poisonous plant species found worldwide. It primarily focuses on the therapeutic potential of specific types of phytochemicals responsible for treating multiple diseases. This review includes a list of 70 poisonous plants with medicinal properties for treating various ailments, as well as some of their traditional uses. A few of these plants are emphasized, which have been tremendously explored and studied, hold significant potential to contribute to modern drug discovery. Furthermore, it addresses the possible prospects and challenges of using poisonous plants and their phytochemicals as therapeutic agents. Although the therapeutic potential of poisonous plants is substantial, many toxins remain unexplored. This review accentuates the need for rigorous scientific investigations, prior to clinical trials to validate their traditional uses, which would reveal the pharmacological interventions that will eventually advance human health and well-being.
Triple Negative Breast Cancer (TNBC) is a highly aggressive type of breast cancer which surpassed the death rate of lung cancer. Hence, discovery of new effective drugs is of immediate clinical need. The objective of the study was to identify and isolate terpenoids from the marine red alga Hypnea valentiae and study its potential cytotoxic and anti-invasive properties in TNBC cell line. The alga was extracted using ethyl acetate. The ethyl acetate extract (HVEA) was separated by column chromatography. The isolated fractions F1 and F2 were characterized by GC-MS. Followed by this F1 and F2 were analyzed for their cytotoxic activity under in vitro conditions in MDA MB 231 cell line using cell proliferative assay and their antimetastatic activity was determined by scratch assay. The outcomes of GC-MS analysis showed that F1 was a terpenoid n-hexadecenoic acid and F2 was a mixture of tetradecanoic acid, n-hexadecenoic acid, cyclohexanol 1-ethnyl carbamate and caryophyllene oxide. The results of in vitro studies showed that HVEA, F1 and F2 exhibited cytotoxicity in MDA-MB 231 cells with IC50 of 10µg/ml, 15µg/ml and 25µg/ml respectively. Further the findings of scratch assay (24hrs) showed that HVEA, F1 and F2 prevented the invasion of cells into the wound area. Overall, the findings of the current investigation suggest that HVEA and isolated terpenoids have potential activity against the survival and invasion of TNBC cells. Hence these compounds may find prominent application in cancer therapy that can be obtained from marine algae.
Syzygium aromaticum L. (clove) is a species native to subtropical countries. Its dried flower buds are rich in essential oils, which have shown insecticidal, anti-inflammatory and anaesthetic effects. This work was aimed to study the differences in antioxidant and anticancer activities between clove essential oil (CEO) and its major component, eugenol. The chemical composition of the CEO was determined by GC-MS. The physicochemical properties and antioxidant activity were determined in CEO and eugenol. Finally, anticancer activities were assayed against seven cell lines. Chemical analysis revealed that 80% of the CEO was eugenol. The density and IR were similar, and the colour was ΔE*>3. CEO had a lower phenolic content, but similar antioxidant activity to eugenol. The anticancer activity of the CEO was greater than that of eugenol in all the cell lines except for HeLa cells. These results suggest that secondary compounds in CEO enhance its antioxidant and -anticancer activities.
Significance: Peroxisome proliferator-activated receptors (PPARs) have a moderately preserved amino-terminal domain, an extremely preserved DNA-binding domain, an integral hinge region, and a distinct ligand-binding domain that are frequently encountered with the other nuclear receptors. PPAR-β/δ is among the three nuclear receptor superfamily members in the PPAR group. Recent Advances: Emerging studies provide an insight on natural compounds that have gained increasing attention as potential anticancer agents due to their ability to target multiple pathways involved in cancer development and progression. Critical Issues: Modulation of PPAR-β/δ activity has been suggested as a potential therapeutic strategy for cancer management. This review focuses on the ability of bioactive phytocompounds to impact reactive oxygen species (ROS) and redox signaling by targeting PPAR-β/δ for cancer therapy. The rise of ROS in cancer cells may play an important part in the initiation and progression of cancer. However, excessive levels of ROS stress can also be toxic to the cells and cancer cells with increased oxidative stress are likely to be more vulnerable to damage by further ROS insults induced by exogenous agents, such as phytocompounds and therapeutic agents. Therefore, redox modulation is a way to selectively kill cancer cells without causing significant toxicity to normal cells. However, use of antioxidants together with cancer drugs may risk the effect of treatment as both act through opposite mechanisms. Future Directions: It is advisable to employ more thorough and detailed methodologies to undertake mechanistic explorations of numerous phytocompounds. Moreover, conducting additional clinical studies is recommended to establish optimal dosages, efficacy, and the impact of different phytochemicals on PPAR-β/δ.
Volatile oil (VO) is the main chemical component of common plants in Chrysanthemum genus, and it possesses several beneficial pharmacological properties, including bacteriostatic, antioxidant, anti-tumor, anti-inflammatory, antipyretic, analgesic, anti-osteoporotic, antihypertensive, sedative, and hypnotic effects. To date, research on the effective components of Chrysanthemum extract has mainly focused on flavonoids, whereas limited data are available on the chemical constituents and underlying mechanisms of action of the VO components. In this review, the pharmacological activities and mechanisms of VO are comprehensively reviewed with the aim of providing a foundation for further development for medicinal, aromatherapy, and diet therapy applications.
Pulmonary hypertension (PH) is a disease that affects the right ventricle and venous circulation. The need for improvement in the discovery of novel therapeutic targets and drugs focusing on the immunomodulatory for the treatment of pulmonary hypertension is very important. Abnormalities in the immune system may result in pulmonary hypertension, and macrophages and Treg may be important targets for the development of novel treatment of pulmonary hypertension. Certainly, the macrophages, Treg, and the immune system have the potential therapeutic benefit by effectively modulating the macrophage to benefit pro-resolving phenotype anti-inflammatory and repair. The multifaceted association of immune system homeostasis, macrophages, and Treg is still debatable. Here, in this review, we highlight the significance of macrophages, Treg, and other immune cells’ functions in pulmonary hypertension. We also considered the Treg and macrophages in the phosphatidyl inositol 3-kinase signaling pathway.
Graphical Abstract
Breast Cancer (BC) is the most prevalent type of cancer in the world. Current treatments include surgery, radiation, and chemotherapy but often are associated with high toxicity to normal tissues, chemoresistance, and relapse. Thus, developing novel therapies which could combat these limitations is essential for effective treatment. In this context, phytochemicals are increasingly getting popular due to their safety profile, ability to efficiently target tumors, and circumvent limitations of existing treatments. Essential Oils (EOs) are mixtures of various phytochemicals which have shown potential anticancer activity in preclinical BC models. However, their clinical translation is limited by factors such as high volatility, low stability, and poor solubility. Nanotechnology has facilitated their encapsulation in a variety of nanostructures and proven to overcome these limitations. In this review, we have efficiently summarized the current knowledge on the anticancer effect of EOs and constituents in both in in vitro and in in vivo BC models. Further, we also provide a descriptive account on the potential of nanotechnology in enhancing the anti‐BC activity of EOs and their constituents. The papers discussed in this review were selected using the keywords “antiproliferative Essential Oils in breast cancer,” “anticancer activity of Essential Oil in breast cancer,” and “cytotoxicity of Essential Oils in breast cancer” performed in PubMed and ScienceDirect databases.
Cancer is a group of heterogeneous diseases that occur when cells in the body proliferate and divide uncontrollably. As the current treatment modalities have pros and cons, the discovery of new chemotherapeutic agents with the least side effects is one of the most investigated research areas. In this context, plant-based natural products are a rich source of drugs and have served humanity for ages. Frankincense essential oils (FEOs) are among the most promising plant-based oils in Gulf countries. In addition to their high cultural value, FEOs are also famous for their engaging biological activities, including anti-cancerous. However, the practical application of FEOs is often hindered/by their low water solubility, limited bioavailability, high volatility, and sensitivity toward heat, humidity, light, or oxygen. Thus, a significant demand for technological advancement would improve their ability to target particular cells and tissues. Nanotechnology emerged as an exciting approach in this context. Through suitable nano-formulation (functionalization or encapsulation into a nanostructure), issues arising due to solubility, targeting capability, and delivery can be controlled.
Volatile oil of Psidium guajava leaves obtained by steam distillation was given orally to study its effects on the exudation and proliferative phases of the inflammatory reaction, using technique of carragenin induced paw edema and cotton pellets in male albino rats. The anti inflammatory activity as compared with ketorolac tromethamine. In carragenin induced edemas,. 0.8ml/kg of the volatile oil ad anti-inflammatory activity as that of ketorolac tromethamine. The oil was also found to be potent in cotton pellet granuom studies. Preliminary investigation revealed that the volatile oil fraction consist sesqueterpene which may be responsible for its anti inflammatory activity.
Phenethyl isothiocyanate (PEITC), a constituent of edible cruciferous vegetables such as watercress, not only affords significant protection against chemically induced cancer in experimental rodents but also inhibits growth of human cancer cells by causing apoptotic and autophagic cell death. However, the underlying mechanism of PEITC-induced cell death is not fully understood. Using LNCaP and PC-3 human prostate cancer cells as a model, we demonstrate that the PEITC-induced cell death is initiated by production of reactive oxygen species (ROS) resulting from inhibition of oxidative phosphorylation (OXPHOS). Exposure of LNCaP and PC-3 cells to pharmacologic concentrations of PEITC resulted in ROS production, which correlated with inhibition of complex III activity, suppression of OXPHOS, and ATP depletion. These effects were not observed in a representative normal human prostate epithelial cell line (PrEC). The ROS production by PEITC treatment was not influenced by cyclosporin A. The Rho-0 variants of LNCaP and PC-3 cells were more resistant to PEITC-mediated ROS generation, apoptotic DNA fragmentation, and collapse of mitochondrial membrane potential compared with respective wild-type cells. The PEITC treatment resulted in activation of Bax in wild-type LNCaP and PC-3 cells, but not in their respective Rho-0 variants. Furthermore, RNA interference of Bax and Bak conferred significant protection against PEITC-induced apoptosis. The Rho-0 variants of LNCaP and PC-3 cells also resisted PEITC-mediated autophagy. In conclusion, the present study provides novel insight into the molecular circuitry of PEITC-induced cell death involving ROS production due to inhibition of complex III and OXPHOS.
Essential oil of star anise as well as phenylpropanoids and sesquiterpenes, for example, trans-anethole, eugenol, β-eudesmol, farnesol, β-caryophyllene and β-caryophyllene oxide, which are present in many essential oils, were examined for their antiviral activity against herpes simplex virus type 1 (HSV-1) in vitro. Antiviral activity was analyzed by plaque reduction assays and mode of antiviral action was determined by addition of the drugs to uninfected cells, to the virus prior to infection or to herpesvirus-infected cells. Star anise oil reduced viral infectivity by >99%, phenylpropanoids inhibited HSV infectivity by about 60-80% and sesquiterpenes suppressed herpes virus infection by 40-98%. Both, star anise essential oil and all isolated compounds exhibited anti-HSV-1 activity by direct inactivation of free virus particles in viral suspension assays. All tested drugs interacted in a dose-dependent manner with herpesvirus particles, thereby inactivating viral infectivity. Star anise oil, rich in trans-anethole, revealed a high selectivity index of 160 against HSV, whereas among the isolated compounds only β-caryophyllene displayed a high selectivity index of 140. The presence of β-caryophyllene in many essential oils might contribute strongly to their antiviral ability. These results indicate that phenylpropanoids and sesquiterpenes present in essential oils contribute to their antiviral activity against HSV.
Thymoquinone (TQ), a component of black seed essential oil, is known to induce apoptotic cell death and oxidative stress, however, the direct involvement of oxidants in TQ-induced cell death has not been established yet. Here, we show that TQ inhibited the proliferation of a panel of human colon cancer cells (Caco-2, HCT-116, LoVo, DLD-1 and HT-29), without exhibiting cytotoxicity to normal human intestinal FHs74Int cells. Further investigation in DLD-1 revealed that apoptotic cell death is the mechanism for TQ-induced growth inhibition as confirmed by flow cytometry, M30 cytodeath and caspase-3/7 activation. Apoptosis was induced via the generation of reactive oxygen species (ROS) as evidenced by the abrogation of TQ apoptotic effect in cells preincubated with the strong antioxidant N-acetyl cysteine (NAC). TQ increased the phosphorylation states of the mitogen-activated protein kinases (MAPK) JNK and ERK, but not of p38. Their activation was completely abolished in the presence of NAC. Using PD98059 and SP600125, specific ERK and JNK inhibitors, the two kinases were found to possess pro-survival activities in TQ-induced cell death. These data present evidence linking the pro-oxidant effects of TQ with its apoptotic effects in colon cancer and prove a protective role of MAPK.
Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m(-2) on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33-69) were entered; 11 had prior taxane therapy for breast (n=5), ovarian (n=3), and vaginal cancer (n=1) or angiosarcoma (n=2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m(-2), warranting further clinical investigation.
Plants use complex mixtures of secondary compounds (SM) of different structural classes to protect themselves against herbivores, bacteria, fungi and viruses. These complex mixtures may contain SM, which are specific for a single target (monotarget SM). A majority of SM, however, can interfere with several targets (multitarget SM) in a pleiotropic fashion. The composition of such extracts appears to be optimised, since the components are not only additive but apparently synergistic in their bioactivity. Synergism can be achieved by inhibiting the xenobiotics inactivating activities of animals and microbes (MDR, CYP), by facilitating the uptake of polar SM across biomembranes and/or by affecting several important organs in animals concomitantly. Phytotherapy employs equally complex extracts of medicinal plants. Arguments were put together that the utilisation of complex mixtures with pleiotropic agents presents a unique therapeutic approach with many advantages over monotarget compounds. Mixtures of multitarget SM, used in phytotherapy include phenolics, tannins, mono- and sequiterpenes, saponins, iridoid glucosides and anthraquinones, but only few of them alkaloids or other toxic monotarget SM.Multitarget effects are caused by SM, which can modulate the three-dimensional structure of proteins (and thus their function), by interfering with DNA/RNA (especially gene expression) or membrane permeability. In addition, complex extracts may contain synergists, which can inhibit MDR, cytochrome P450 or enhance absorption and thus bioavailability of active metabolites. The molecular modes of action are reviewed for the main groups of secondary metabolites.
Mitogen-activated protein kinase dual-specificity phosphatase-1 (also called MKP-1, DUSP1, ERP, CL100, HVH1, PTPN10, and 3CH134) is a member of the threonine-tyrosine dual-specificity phosphatases, one of more than 100 protein tyrosine phosphatases. It was first identified approximately 20 years ago, and since that time extensive investigations into both mkp-1 mRNA and protein regulation and function in different cells, tissues, and organs have been conducted. However, no general review on the topic of MKP-1 exists. As the subject matter pertaining to MKP-1 encompasses many branches of the biomedical field, we focus on the role of this protein in cancer development and progression, highlighting the potential role of the mitogen-activated protein kinase (MAPK) family. Section II of this article elucidates the MAPK family cross-talk. Section III reviews the structure of the mkp-1 encoding gene, and the known mechanisms regulating the expression and activity of the protein. Section IV is an overview of the MAPK-specific dual-specificity phosphatases and their role in cancer. In sections V and VI, mkp-1 mRNA and protein are examined in relation to cancer biology, therapeutics, and clinical studies, including a discussion of the potential role of the MAPK family. We conclude by proposing an integrated scheme for MKP-1 and MAPK in cancer.
Benzyl isothiocyanate (BITC), a dietary cancer chemopreventive agent, causes apoptosis in MDA-MB-231 and MCF-7 human breast cancer cells, but the mechanism of cell death is not fully understood. We now demonstrate that the BITC-induced apoptosis in human breast cancer cells is initiated by reactive oxygen species (ROS) due to inhibition of complex III of the mitochondrial respiratory chain. The BITC-induced ROS production and apoptosis were significantly inhibited by overexpression of catalase and Cu,Zn-superoxide dismutase and pharmacological inhibition of the mitochondrial respiratory chain. The mitochondrial DNA-deficient Rho-0 variant of MDA-MB-231 cells was nearly completely resistant to BITC-mediated ROS generation and apoptosis. The Rho-0 MDA-MB-231 cells also resisted BITC-mediated mitochondrial translocation (activation) of Bax. Biochemical assays revealed inhibition of complex III activity in BITC-treated MDA-MB-231 cells as early as at 1 h of treatment. The BITC treatment caused activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), which function upstream of Bax activation in apoptotic response to various stimuli. Pharmacological inhibition of both JNK and p38 MAPK conferred partial yet significant protection against BITC-induced apoptosis. Activation of JNK and p38 MAPK resulting from BITC exposure was abolished by overexpression of catalase. The BITC-mediated conformational change of Bax was markedly suppressed by ectopic expression of catalytically inactive mutant of JNK kinase 2 (JNKK2(AA)). Interestingly, a normal human mammary epithelial cell line was resistant to BITC-mediated ROS generation, JNK/p38 MAPK activation, and apoptosis. In conclusion, the present study indicates that the BITC-induced apoptosis in human breast cancer cells is initiated by mitochondria-derived ROS.
The mechanisms of UVB-induced apoptosis and the role of p38 mitogen-activated protein kinase (MAPK) were investigated in HaCaT cells. UVB doses that induced apoptosis also produced a sustained activation of p38 MAPK and mitochondrial cytochrome c release, leading to pro-caspase-3 activation. Late into the apoptotic process, UVB also induced a caspase-mediated cleavage of Bid. Caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone substantially blocked the UVB-induced apoptosis without preventing the release of mitochondrial cytochrome c and the p38 MAPK activation. The inhibition of p38 MAPK counteracted both apoptosis and cytochrome c release as well as the DEVD-amino-4-methylcoumarin cleavage activity without affecting the processing of pro-caspase-8. These results indicate that UVB induces multiple and independent apoptotic pathways, which culminate in pro-caspase-3 activation, and that the initial cytochrome c release is independent of caspase activity. Importantly, we show that a sustained p38 MAPK activation contributes to the UVB-induced apoptosis by mediating the release of mitochondrial cytochrome c into the cytosol.
The c-Jun NH2-terminal kinase (JNK) is activated when cells are exposed to ultraviolet (UV) radiation. However, the functional consequence
of JNK activation in UV-irradiated cells has not been established. It is shown here that JNK is required for UV-induced apoptosis
in primary murine embryonic fibroblasts. Fibroblasts with simultaneous targeted disruptions of all the functional Jnkgenes were protected against UV-stimulated apoptosis. The absence of JNK caused a defect in the mitochondrial death signaling
pathway, including the failure to release cytochrome c. These data indicate that mitochondria are influenced by proapoptotic
signal transduction through the JNK pathway.
The serine/threonine kinase Akt/PKB is a potent regulator of cell survival and has oncogenic transformation potential. Previously, it has been shown that Akt can activate the transcription factor NF-kappaB and that this functions to block apoptosis induced by certain stimuli. The mechanism whereby Akt activates NF-kappaB has been controversial, with evidence supporting induction of nuclear translocation of NF-kappaB via activation of IkappaB kinase activity and/or the stimulation of the transcription function of NF-kappaB. Here we demonstrate that Akt targets the transactivation function of NF-kappaB by stimulating the transactivation domain of RelA/p65 in a manner that is dependent on IkappaB kinase beta activity and on the mitogen-activated protein kinase p38 (p38). Activation of RelA/p65 transactivation function requires serines 529 and 536, sites shown previously to be inducibly phosphorylated. Consistent with the requirement of p38 in the activation of NF-kappaB transcriptional function, expression of activated Akt induces p38 activity. Furthermore, the ability of IL-1beta to activate NF-kappaB is known to involve Akt, and we show here that IL-1beta induces p38 activity in manner dependent on Akt and IkappaB kinase activation. Interestingly, activated Akt and the transcriptional co-activators CBP/p300 synergize in the activation of the RelA/p65 transactivation domain, and this synergy is blocked by p38 inhibitors. These studies demonstrate that Akt, functioning through IkappaB kinase and p38, induces the transcription function of NF-kappaB by stimulating the RelA/p65 transactivation subunit of NF-kappaB.
The mechanisms by which prostate cancer (PCa) cells progress to a hormone refractory state are poorly understood. The progression process under androgen ablation conditions involves the survival of at least a portion of malignant cells and their eventual proliferation in an androgen-independent manner. The goal of this study was to investigate the role of PI3K signaling in such a progression. Using an in vitro model of androgen ablation, we show that after removal of androgen support, the human PCa cell line LNCaP initially arrested in G(1) and trans-differentiated into neuroendocrine-like cells that eventually resumed androgen-independent proliferation. Both acute and chronic androgen ablation resulted in an increase in basal levels of PI3K and Akt activity, which were sustained throughout the progression process. Under these conditions, inhibition of PI3K, pharmacologically or with ectopic expression of PTEN, arrested cell proliferation and blocked progression to the androgen-independent state. In contrast, LNCaP cells in the presence of androgens were marginally sensitive to PI3K inhibition. During the chronic stage of androgen deprivation, androgen-independent proliferation correlated with diminished p27(kip1) protein levels, whereas PI3K and Akt activity remained elevated. At this stage, PI3K inhibition rapidly triggered accumulation of p27(kip1), cell cycle arrest, and cell death. PI3K modulated p27(kip1) levels at least in part by regulating its rate of degradation. Taken together, these data show that androgen ablation alone can increase PI3K-Akt activation, which supports survival after acute androgen ablation and proliferation during chronic androgen deprivation. Successful progression to the androgen-independent state in the LNCaP cell line model requires intact PI3K signaling.
Toll-like receptor-4 (TLR4) can be activated by nonbacterial agonists, including saturated fatty acids. However, downstream signaling pathways activated by nonbacterial agonists are not known. Thus, we determined the downstream signaling pathways derived from saturated fatty acid-induced TLR4 activation. Saturated fatty acid (lauric acid)-induced NFkappaB activation was inhibited by a dominant-negative mutant of TLR4, MyD88, IRAK-1, TRAF6, or IkappaBalpha in macrophages (RAW264.7) and 293T cells transfected with TLR4 and MD2. Lauric acid induced the transient phosphorylation of AKT. LY294002, dominant-negative (DN) phosphatidylinositol 3-kinase (PI3K), or AKT(DN) inhibited NFkappaB activation, p65 transactivation, and cyclooxygenase-2 (COX-2) expression induced by lauric acid or constitutively active (CA) TLR4. AKT(DN) blocked MyD88-induced NFkappaB activation, suggesting that AKT is a MyD88-dependent downstream signaling component of TLR4. AKT(CA) was sufficient to induce NFkappaB activation and COX-2 expression. These results demonstrate that NFkappaB activation and COX-2 expression induced by lauric acid are at least partly mediated through the TLR4/PI3K/AKT signaling pathway. In contrast, docosahexaenoic acid (DHA) inhibited the phosphorylation of AKT induced by lipopolysaccharide or lauric acid. DHA also suppressed NFkappaB activation induced by TLR4(CA), but not MyD88(CA) or AKT(CA), suggesting that the molecular targets of DHA are signaling components upstream of MyD88 and AKT. Together, these results suggest that saturated and polyunsaturated fatty acids reciprocally modulate the activation of TLR4 and its downstream signaling pathways involving MyD88/IRAK/TRAF6 and PI3K/AKT and further suggest the possibility that TLR4-mediated target gene expression and cellular responses are also differentially modulated by saturated and unsaturated fatty acids.
Subtraction hybridization identified melanoma differentiation associated gene-7, mda-7, in the context of terminally differentiated human melanoma cells. Based on its structure, cytokine-like properties and proposed mode of action, mda-7 has now been classified as IL-24. When expressed by means of a replication-incompetent adenovirus, Ad.mda-7 induces apoptosis in a broad range of cancer cells, without inducing harmful effects in normal fibroblast or epithelial cells. These unique properties of mda-7/IL-24 suggest that this gene will prove beneficial for cancer gene therapy. We now demonstrate that Ad.mda-7 decreases viability by induction of apoptosis in hormone-responsive (LNCaP) and hormone-independent (DU-145 and PC-3) human prostate carcinomas, without altering growth or survival in early-passage normal human prostate epithelial cells (HuPEC). Ad.mda-7 causes G(2)/M arrest and apoptosis in LNCaP (p53-wildtype), DU-145 (p53 mutant, Bax-negative) and PC-3 (p53-negative) prostate carcinomas, but not in HuPEC. Apoptosis induction correlated with changes in the ratio of pro- to antiapoptotic Bcl-2 protein family members. A potential functional role for changes in bcl-2 family gene expression in Ad.mda-7-induced apoptosis was suggested by the finding that forced overexpression of bcl-x(L) or bcl-2 differentially diminished the apoptotic effect of Ad.mda-7 in prostate carcinomas. These results confirm that induction of apoptosis by the mda-7/IL-24 gene in prostate cancer cells is Bax- and p53-independent and is mediated by mitochondrial pathways involving bcl-2 family gene members. The mda-7/IL-24 gene represents a new class of cancer-specific apoptosis-inducing genes with obvious potential for the targeted gene-based therapy of human prostate cancer.
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays important roles for prostate cancer cell survival, and the androgen
receptor (AR) plays essential roles for prostate cancer cell proliferation. How these two signals cooperate to control cell
growth and death, however, remains unclear and debated. Here we provide the first linkage by the identification of Forkhead
transcription factor FOXO3a, the PI3K/Akt downstream substrate, as a positive regulator for the induction of AR gene expression.
Both Western blot and real time PCR assays demonstrate that FOXO3a can induce AR expression at the protein and mRNA levels,
and gel shift and chromatin immunoprecipitation assays further demonstrate that FOXO3a can induce 5′ AR promoter activity
via binding to the consensus DNA-binding sequence in the AR 5′ promoter -1290 to -1297 (5′-TTGTTTCA-3′). Under normal growth
conditions, blocking PI3K/Akt signals by LY294002 causes LNCaP cell arrest in G1 phase rather than apoptosis. However, further blocking of AR functions by AR small interfering RNA leads to dramatic LNCaP
cell death, suggesting that AR may play important protective roles when the PI3K/Akt signal pathway is blocked by LY294002.
Together, our data provide the first model to explain how PI3K/Akt and AR can cooperate to control LNCaP cell growth and death
under normal conditions.
The cytotoxicity of three extracts (petroleum ether, ethyl acetate and n-butanol) from a plant used in folk medicine, Marchantia convoluta, to human non-small cell lung carcinoma (H1299) and liver carcinoma (HepG2) cell lines was tested. After 72-h incubation of lung and liver cancer cell cultures with varying concentrations of extracts (15 to 200 microg/mL), cytotoxicity was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and reported in terms of cell viability. The extracts that showed a significant cytotoxicity were subjected to gas chromatography-mass spectrometry analysis to identify the components. The ethyl acetate, but not the petroleum ether or n-butanol extract, had a significant cytotoxicity against lung and liver carcinoma cells with IC50 values of 100 and 30 microg/mL, respectively. A high concentration of ethyl acetate extract (100 microg/mL) rapidly reduced the number of H1299 cells. At lower concentrations of ethyl acetate extract (15, 30, and 40 microg/mL), the numbers of HepG2 cells started to decrease markedly. Gas chromatography-mass spectrometry analysis of the ethyl acetate extract revealed the presence of several compounds such as phytol (23.42%), 1,2,4-tripropylbenzene (13.09%), 9-cedranone (12.75%), ledene oxide (7.22%), caryophyllene (1.82%), and caryophyllene oxide (1.15%). HPLC analysis result showed that there were no flavonoids in ethyl acetate extract, but flavonoids are abundant in n-butanol extract. Further studies are needed regarding the identification, toxicity, and mechanism of action of active compounds.
The mechanisms by which prostate cancer (PCa) cells progress to a hormone refractory state are poorly understood. The progression process under androgen ablation conditions involves the survival of at least a portion of malignant cells and their eventual proliferation in an androgen-independent manner. The goal of this study was to investigate the role of PI3K signaling in such a progression. Using an in vitro model of androgen ablation, we show that after removal of androgen support, the human PCa cell line LNCaP initially arrested in G(1) and trans-differentiated into neuroendocrine-like cells that eventually resumed androgen-independent proliferation. Both acute and chronic androgen ablation resulted in an increase in basal levels of PI3K and Akt activity, which were sustained throughout the progression process. Under these conditions, inhibition of PI3K, pharmacologically or with ectopic expression of PTEN, arrested cell proliferation and blocked progression to the androgen-independent state. In contrast, LNCaP cells in the presence of androgens were marginally sensitive to PI3K inhibition. During the chronic stage of androgen deprivation, androgen-independent proliferation correlated with diminished p27(kip1) protein levels, whereas PI3K and Akt activity remained elevated. At this stage, PI3K inhibition rapidly triggered accumulation of p27(kip1), cell cycle arrest, and cell death. PI3K modulated p27(kip1) levels at least in part by regulating its rate of degradation. Taken together, these data show that androgen ablation alone can increase PI3K-Akt activation, which supports survival after acute androgen ablation and proliferation during chronic androgen deprivation. Successful progression to the androgen-independent state in the LNCaP cell line model requires intact PI3K signaling.
The c-Jun NH2-terminal kinase (JNK) is activated when cells are exposed to ultraviolet (UV) radiation. However, the functional consequence of JNK activation in UV-irradiated cells has not been established. It is shown here that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts. Fibroblasts with simultaneous targeted disruptions of all the functional Jnk genes were protected against UV-stimulated apoptosis. The absence of JNK caused a defect in the mitochondrial death signaling pathway, including the failure to release cytochrome c. These data indicate that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.
Thymoquinone (TQ), a component of black seed essential oil, is known to induce apoptotic cell death and oxidative stress, however, the direct involvement of oxidants in TQ-induced cell death has not been established yet. Here, we show that TQ inhibited the proliferation of a panel of human colon cancer cells (Caco-2, HCT-116, LoVo, DLD-1 and HT-29), without exhibiting cytotoxicity to normal human intestinal FHs74Int cells. Further investigation in DLD-1 revealed that apoptotic cell death is the mechanism for TQ-induced growth inhibition as confirmed by flow cytometry, M30 cytodeath and caspase-3/7 activation. Apoptosis was induced via the generation of reac-tive oxygen species (ROS) as evidenced by the abrogation of TQ apoptotic effect in cells preincubated with the strong antioxidant N-acetyl cysteine (NAC). TQ increased the phosphorylation states of the mitogen-activated protein kinases (MAPK) JNK and ERK, but not of p38. Their activation was completely abolished in the presence of NAC. Using PD98059 and SP600125, specific ERK and JNK inhibitors, the two kinases were found to possess pro-survival activities in TQ-induced cell death. These data present evidence linking the pro-oxidant effects of TQ with its apoptotic effects in colon cancer and prove a protective role of MAPK.
β-caryophyllene oxide was isolated from the leaf of the Jeju guava (Psidium cattleianum Sabine) for the first time in this study. The chemical structure was confirmed with the help of various spectroscopic analyses, including NMR data, by comparison to that of the published data. An MTT assay was conducted against several cancer cell lines to resolve an ongoing controversy regarding the cytotoxic effects of β- caryophyllene oxide. β-caryophyllene oxide evidenced potent cytotoxic activity against HepG2, AGS, HeLa, SNU-1, and SNU-16 cells, with IC 50 values of 3.95, 12.6, 13.55, 16.79, and 27.39 μM, respectively. The results also showed that β-caryophyllene oxide evidenced cytotoxicity in both a dose-dependent and time-dependent manner.
The methanolic fraction of Psidium guajava fruit extract was found to possess significant inhibitory activity against carragenin, kaolin and turpentine-induced oedema formation. The fraction significantly inhibited protein exudation. The proliferative form of inflammation was significantly counteracted following cotton pellet-induced granuloma formation in rats. Acetic acid-induced algesia (writhing) in mice was significantly inhibited by the fraction. Significant antipyretic activity of the fraction was observed following yeast-induced pyrexia in rats. Potent antiarthritic activity was observed with the fraction against formaldehyde-induced chronic arthritis in rats.
The phosphatidylinositol 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathway regulates a broad spectrum of physiologic and pathologic processes. In breast cancer mutation, amplification, deletion, methylation, and posttranslational modifications lead to significant dysregulation of this pathway leading to more aggressive and potentially drug-resistant disease. Multiple novel agents, targeting different nodes within the pathway are currently under development by both commercial and academic partners. The key to the successful validation of these markers is selection of the appropriate patient groups using biomarkers. This article reviews current progress in this area, highlighting the key molecular alterations described in genes within the PI3K/Akt/mTOR pathway that may have an effect on response to current and future therapeutic interventions. Herein, gaps in current knowledge are highlighted and suggestions for future research directions given that may facilitate biomarker development in partnership with current drug development.
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway mediates multiple cellular functions critical to tumor initiation, progression, and outcomes, including growth and proliferation, metabolism, motility, migration, invasion, angiogenesis, survival, and autophagy. Tight regulation of this pathway is paramount to ensure that multiple cellular inputs are integrated for appropriate cellular outcomes. Frequent deregulation and aberrations of this pathway have been implicated in breast cancer development and progression. This review focuses on the biology of this pathway and its role in breast cancer pathogenesis. The role of therapies directed at targeting mTOR in the PI3K/Akt/mTOR pathway, which are currently being evaluated in clinical trials, will also be reviewed.
The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway mediates the effects of a variety of extracellular signals in a number of cellular processes including cell growth, proliferation, and survival. The alteration of integrants of this pathway through mutation of its coding genes increases the activation status of the signaling and can thus lead to cellular transformation. The frequent dysregulation of the PI3K/Akt pathway in breast cancer (BC) and the mediation of this pathway in different processes characteristically implicated in tumorigenesis have attracted the interest of this pathway in BC; however, a more comprehensive understanding of the signaling intricacies is necessary to develop clinical applications of the modulation of this pathway in this pathology. We review a series of experiments examining the contribution of alteration of integrants of this signaling network to human BC and we make an update of the information about the effect of the modulation of this pathway in this cancer.
Aqueous extract of Psidium guajava L. budding leaves (PE) has been shown to possess anti-prostate cancer activity in a cell line model. We examined whether its bioactivity could be conserved either in the presence or the absence of synthetic androgen R1881. In both cases, PE was shown to inhibit LNCaP cell proliferation and down-regulate expressions of androgen receptor (AR) and prostate specific antigen (PSA). The cytotoxicity of PE was shown by enhanced LDH release in LNCaP cells. The flow cytometry analysis revealed cell cycle arrests at G(0)/G(1) phase with huge amount of apoptotic LNCaP cells after treatment with PE for 48 h in a dose-responsive manner, which was also confirmed by TUNEL assay. From the results of decreased Bcl-2/Bax ratio, inactivation of phosphor-Akt, activation of phosphor-p38, phospho-Erk1/phospho-Erk2, the molecular action mechanism of PE to induce apoptosis in LNCaP cells was elucidated. Compatible with the in vitro study findings, treatment with PE (1.5 mg/mouse/day) significantly diminished both the PSA serum levels and tumor size in a xenograft mouse tumor model. Conclusively, PE is a promising anti-androgen-sensative prostate cancer agent.
Berberine, an isoquinoline plant alkaloid, has been known to generate a wide variety of biochemical and pharmacological effects. In order to elucidate the molecular mechanism for the berberine-induced enhancement of radio-sensitization, the human hepatoma HepG2 cells were treated with berberine combined with irradiation. The anti-tumor effect of gamma radiation was found to be significantly enhanced by berberine. The evidences of apoptosis, such as apoptotic DNA fragmentation and annexin V staining, were observed in the cells treated with the combination of berberine and irradiation. Additionally, the levels of reactive oxygen species (ROS) and nitric oxide (NO) were apparently elevated in the combination system. The activations of p38, Bax, and caspase-3 were also detected in the irradiated cells pretreated with berberine. The productions of ROS and annexin V staining in the cells treated with the combination of berberine and irradiation were significantly inhibited by the specific inhibitor of p38 MAPK, SB203580. The cell death induced by berberine alone or the combination of berberine and irradiation was suppressed by the anti-oxidant, N-acetyl cysteine (NAC). Taken together, the present results clearly indicate that the combination of berberine and gamma-radiation enhance the anti-cancer effects through the p38 MAPK pathway and ROS generation.
Mammalian target of rapamycin (mTOR) is a key protein kinase controlling signal transduction from various growth factors and upstream proteins to the level of mRNA and ribosome with a regulatory effect on cell cycle progression, cellular proliferation and growth. TOR genes were discovered rather serendipitously while investigating the cause of resistance to immunosuppressant rapamycin in yeast. In normal cells, mTOR controls brilliantly the load of signals from its effectors resulting in a normal cell function. On the contrary, in various diseases and mainly in cancer this balance is lost due to mutations or overactivation of upstream pathways leading to a persistent proliferation and tumor growth. What makes mTOR attractive to researchers seems to be its key position which is on the crossroad of various signal pathways (Ras, PI3K/Akt, TSC, NF-kappaB) towards mRNA, ribosome, protein synthesis and translation of significant molecules, the uncontrolled production of which may lead to tumor proliferation and growth. Inhibition of mTOR by rapamycin (a natural product) or its analogs aims to prevent the deleterious effects of the abnormal signaling, regardless at which point of the signal pathway has the abnormality launched. Here, we will review the physiological functions of mTOR, its association to carcinogenesis and the latest evidence regarding the use of mTOR inhibitors in cancer treatment as well as future trends and aims of research.
The relative distribution of androgen (AR), progesterone (PR), and estrogen receptors (ER) was localized and estimated in human prostate tissue by immunohistochemistry in five normal tissue samples, in eight benign hyperplastic (BPH) samples, in nine primary cancers, and in seven prostate cancer metastases. Moreover, three prostatic cancer cell lines (LNCaP, DU 145, and PC 3) were analyzed. A comparison between the results obtained by radioligand binding assays and immunohistochemistry was performed for the AR and PR.
Using immunohistochemistry, the AR was exclusively detected in the nuclei of both benign and malignant prostatic epithelial cells. The highest proportion of AR-positive cells was found in BPH and in prostate cancer metastases as compared with normal prostatic tissue. In a majority of the cases, the PR was only present in the nuclei of stromal cells. Benign hyperplastic prostates contained higher proportions of PR-positive cells as compared with primary carcinoma. PR was sparse in epithelial cells. ER-positive stromal cell nuclei were only detected in carcinomatous prostates. A few ER-positive epithelial cell nuclei were found in one sample each of a BPH and normal prostate.
All cells from the androgen-dependent, LNCaP, cell line and a majority of the cells from the androgen-independent, DU 145, cell line were AR-positive. In contrast, the cells from the androgen-independent, PC 3, cell line were all AR-negative. All three cell lines were PR- and ER-negative.
The radioligand binding technique detected the AR in extracts from both the cytosol and the nucleus. Again BPH contained higher amounts of AR as compared with normal prostatic tissue. The LNCaP cells contained high amounts of cytosolic AR while cells from the DU 145 and PC 3 cell lines lacked detectable AR as estimated by biochemical techniques. There seemed to be a discrepancy between biochemically measured and immunohistochemically estimated receptor content.
Bioassay-directed fractionation of clove terpenes from the plant Eugenia caryophyllata has led to the isolation of the following five active known compounds: beta-caryophyllene [1], beta-caryophyllene oxide [2], alpha-humulene [3], alpha-humulene epoxide I [4], and eugenol [5]. Their structures were determined on the basis of spectral analysis (hreims, 1H and 13C nmr). These compounds showed significant activity as inducers of the detoxifying enzyme glutathione S-transferase in the mouse liver and small intestine. The ability of natural anticarcinogens to induce detoxifying enzymes has been found to correlate with their activity in the inhibition of chemical carcinogenesis. Thus, these sesquiterpenes show promise as potential anticarcinogenic agents.
A fragment of a complementary DNA (cDNA) clone for human prostatic acid phosphatase (PAP) (EC 3.1.3.2.) was used to study the expression of corresponding mRNA in human tissues. The specificity of its expression in benign prostatic hyperplasia (BPH) and prostatic carcinoma tissues were indicated in RNA blot analyses. The PAPcDNA probe did not recognize any specific mRNAs in RNAs extracted from human liver cancer, lung cancer, pancreatic cancer, placenta, breast cancer cells (MCF-7), mononuclear blood cells or acute promyelocytic leukemia cells (HL-60), according to Northern blot analysis. mRNA for PAP was detected in the androgen-dependent human prostatic cancer cell line LNCaP, but not in the androgen-insensitive human prostatic cancer cell line PC-3. In contrast, lysosomal acid phosphatase (LAP) mRNA was detected in both of these human prostatic cancer cell lines. Our findings indicate a high specificity for the PAP gene in prostatic tissue. The mean abundance for the PAPmRNA expression was 0.26 for prostatic carcinoma samples (n = 11) and 0.46 for BPH samples (n = 8) according to slot-blot analysis. The differences observed between the different categories of prostatic tissue in PAPmRNA abundances call for additional studies on regulation of its expression.
Three mouse cyclin-like (CYL) genes were isolated, two of which are regulated by colony-stimulating factor 1 (CSF-1) during the G1 phase of the macrophage cell cycle. CSF-1 deprivation during G1 leads to rapid degradation of CYL proteins (p36CYL) and correlates with failure to initiate DNA synthesis. However, after entering S phase, macrophages no longer require CSF-1 and can complete cell division without expressing CYL genes. During G1, p36CYL is phosphorylated and associates with a polypeptide antigenically related to p34cdc2. The timing of p36CYL expression, its rapid turnover in the absence of CSF-1, and its phosphorylation and transient binding to a cdc2-related polypeptide suggest that CYL genes may function during S phase commitment.
The tumor-suppressor gene p53 is altered by missense mutation in numerous human malignancies. However, the biochemical properties
of p53 and the effect of mutation on these properties are unclear. A human DNA sequence was identified that binds specifically
to wild-type human p53 protein in vitro. As few as 33 base pairs were sufficient to confer specific binding. Certain guanines
within this 33-base pair region were critical, as methylation of these guanines or their substitution with thymine-abrogated
binding. Human p53 proteins containing either of two missense mutations commonly found in human tumors were unable to bind
significantly to this sequence. These data suggest that a function of p53 may be mediated by its ability to bind to specific
DNA sequences in the human genome, and that this activity is altered by mutations that occur in human tumors.
The anti-inflammatory active fraction of the Paraguayan crude drug, "Alhucema," Lavandula latifolia Vill. afforded four compounds: coumarin (1), 7-methoxycoumarin (2), trans-phytol (3) and caryophyllene oxide (4). 1 showed a weakly inhibitory effect on carrageenin-induced paw edema in rats on topical application and 4 showed an inhibitory effect on histamine-induced contraction in guinea pig ileum.
The expression of prostatic acid phosphatase (PAcP) in three human prostate carcinoma cell lines including LNCaP, DU 145 and PC-3, was studied to explore its potential role as a marker in the progression of prostate cancer. Although Southern blot analysis suggested the presence of PAcP gene in all three prostate carcinoma cell lines, the Northern blot analysis and the reverse transcriptase-polymerase chain reaction (RT-PCR) assay showed that PAcP mRNA can be detected only in LNCaP cells. As one of the major differences between LNCaP cells and PC-3 as well as DU 145 cells is the androgen-sensitivity of LNCaP cells, we then focused on the influence of PAcP expression by the presence of androgen receptor (AR) in human AR cDNA-transfected PC-3 cells and high passages of LNCaP cells. The results demonstrated that the transfection of human AR cDNA into PC-3 cells did not have any detectable effect on the expression of PAcP. Further, in LNCaP cells, while the level of PAcP mRNA diminished upon passage, the AR mRNA level remained approximately the same. Together, these data suggested that the differential expression of PAcP in different prostate carcinoma cells including high passages of LNCaP cells may occur at the transcriptional level and may have little linkage to the expression of AR.
Mammalian cell-cycle control by antimitogenic signals involves p21Cip1/WAF1 (refs 1-4), p27Kip1 (refs 5, 6) and p57Kip2 (refs 7, 8), a family of proteins that bind to and inhibit cyclin-dependent kinases (CDKs) required for initiation of S phase. The protein p21 also binds to the DNA polymerase delta processivity factor, proliferating-cell nuclear antigen (PCNA), and inhibits in vitro PCNA-dependent DNA replication. The CDK and PCNA inhibitory activities of p21 are shown here to be functionally independent and to reside in separate protein domains. The PCNA binding and inhibitory activities, which are not observed with p27 or p57, reside in the C-terminal domain of p21, whereas the CDK inhibitory activity resides in the conserved N-terminal domains of these proteins. When separately overexpressed in mammalian cells, the CDK and PCNA inhibitory domains prevent DNA replication, demonstrating a dual function of p21 as a cell-cycle inhibitor in vivo.
The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents. Introduction of WAF1 cDNA suppressed the growth of human brain, lung, and colon tumor cells in culture. Using a yeast enhancer trap, a p53-binding site was identified 2.4 kb upstream of WAF1 coding sequences. The WAF1 promoter, including this p53-binding site, conferred p53-dependent inducibility upon a heterologous reporter gene. These studies define a gene whose expression is directly induced by p53 and that could be an important mediator of p53-dependent tumor growth suppression.
Four sesquiterpenoids, beta-caryophyllene, beta-caryophyllene 4,5 alpha-oxide, 7-hydroxy-3,4-dihydrocadalin, and 7-hydroxycadalin, isolated from the dried flower of Heterotheca inuloides Cass. (Asteraceae), have been found to exhibit cytotoxic activity against several solid tumor cell lines. Among them, 7-hydroxy-3,4-dihydrocadalin and 7-hydroxycadalin have also been found to inhibit autoxidative and microsomal lipid peroxidation.
The activation of p70s6k is accompanied by a complex series of phosphorylation events. In this review we propose a model of activation which divides p70s6k into four functional modules that cooperate in leading to full enzyme activity. In the light of the model, we suggest how candidate effectors of p70s6k activation might function by directing the phosphorylation of specific sites.
The mitogen-activated protein (MAP) kinases are a large family of proline-directed, serine/threonine kinases that require tyrosine and threonine phosphorylation of a TxY motif in the activation loop for activation through a phosphorylation cascade involving a MAPKKK, MAPKK and MAPK, often referred to as the MAP kinase module. Three separate such modules have been identified, based on the TxY motif of the MAP kinase and the dual-specificity kinases that strictly phosphorylate their specific TxY sequence. They are the extracellular signal regulated kinases (ERKs), c-jun N-terminal kinases (JNKs) and p38 MAPKs. The ERKs are mainly associated with proliferation and differentiation while the JNKs and p38MAP kinases regulate responses to cellular stresses.
Redox homeostasis is critical for proper cellular function. While reactive oxygen species (ROS) and oxidative stress have been implicated in injury, a rapidly growing literature suggests that a transient increase in ROS levels is an important mediator of proliferation and results in activation of various signaling molecules and pathways, among which the MAP kinases. This review will summarize the role of ROS in MAP kinase activation in various systems, including in macrophages, cells of myeloid origin that play an essential role in inflammation and express a multi-component NADPH oxidase that catalyzes the receptor-regulated production of ROS.
During the course of tumor progression, cancer cells acquire a number of characteristic alterations. These include the capacities to proliferate independently of exogenous growth-promoting or growth-inhibitory signals, to invade surrounding tissues and metastasize to distant sites, to elicit an angiogenic response, and to evade mechanisms that limit cell proliferation, such as apoptosis and replicative senescence. These properties reflect alterations in the cellular signaling pathways that in normal cells control cell proliferation, motility, and survival. Many of the proteins currently under investigation as possible targets for cancer therapy are signaling proteins that are components of these pathways. The nature of these signaling pathways and their roles in tumorigenesis were the subject of a recent Beatson International Cancer Conference.
A novel quinonoid terpenoid, (-)- alpha-tocospirone, a new chromanone, (-)-gynuraone, as well as three new steroids, (22 E,24 S)-7 alpha-hydroperoxystigmasta-5,22-dien-3 beta-ol, (22 E,24 S)-stigmasta-1,4,22-trien-3-one, and (24 R)-stigmasta-1,4-dien-3-one, together with 15 known components, were isolated from the rhizome of Formosan Gynura japonica. Structures of the new compounds were determined through spectral analyses and chemical evidence. Several of the isolated compounds, caryophyllene oxide, 6-acetyl-2,2-dimethylchroman-4-one, vanillin, 2,6-dimethoxy-1,4-benzoquinone, and benzoic acid exhibited significant anti-platelet aggregation activity in vitro.
Prostate cancer is one of the most common cancers among men. Recent studies demonstrated that PI3K signaling is an important intracellular mediator which is involved in multiple cellular functions including proliferation, differentiation, anti-apoptosis, tumorigenesis, and angiogenesis. In the present study, we demonstrate that the inhibition of PI3K activity by LY294002, inhibited prostate cancer cell proliferation and induced the G(1) cell cycle arrest. This effect was accompanied by the decreased expression of G(1)-associated proteins including cyclin D1, CDK4, and Rb phosphorylation at Ser780, Ser795, and Ser807/811, whereas expression of CDK6 and beta-actin was not affected by LY294002. The expression of cyclin kinase inhibitor, p21(CIP1/WAF1), was induced by LY294002, while levels of p16(INK4) were decreased in the same experiment. The inhibition of PI3K activity also inhibited the phosphorylation and p70(S6K), but not MAPK. PI3K regulates cell cycle through AKT, mTOR to p70(S6K). The mTOR inhibitor rapamycin has similar inhibitory effects on G(1) cell cycle progression and expression of cyclin D1, CDK4, and Rb phosphorylation. These results suggest that PI3K mediates G(1) cell cycle progression and cyclin expression through the activation of AKT/mTOR/p70(S6K) signaling pathway in the prostate cancer cells.
Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.
The mammalian target of rapamycin (mTOR) has a central role in the regulation of cell growth. mTOR receives input from multiple signaling pathways, including growth factors and nutrients, to stimulate protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase and eukaryote initiation factor 4E binding protein 1. High levels of dysregulated mTOR activity are associated with several hamartoma syndromes, including tuberous sclerosis complex, the PTEN-related hamartoma syndromes and Peutz-Jeghers syndrome. These disorders are all caused by mutations in tumor-suppressor genes that negatively regulate mTOR. Here we discuss the emerging evidence for a functional relationship between the mTOR signaling pathway and several genetic diseases, and we present evidence supporting a model in which dysregulation of mTOR may be a common molecular basis, not only for hamartoma syndromes, but also for other cellular hypertrophic disorders.
Both extra- and intracellular stimuli elicit a wide variety of responses, such as cell survival, proliferation, differentiation, and apoptosis, through regulation of cell signaling. Recent studies have revealed that stress-responsive signal transduction pathways are strictly regulated by the intracellular redox state. The redox state of the cell is a consequence of the precise balance between the levels of oxidizing and reducing equivalents, such as reactive oxygen species (ROS) and endogenous antioxidants. The generation of ROS fluctuates in response to alterations of both external and internal environment and, in turn, triggers specific signaling cascades, including mitogen-activated protein kinases, which determine cell survival or cell death. This review focuses on the regulatory mechanisms of stress-responsive protein kinases and their involvement in oxidative stress-induced apoptosis. It also provides recent findings on the molecular mechanisms by which redox signaling cross-talks with stress-responsive protein kinase cascades.
Resistance to antiandrogen therapy in patients with metastatic prostate cancer poses a major challenge, which, if overcome, may lead to significant advances in the treatment of these patients. Hormone resistance of prostate cancer develops, in part, from upregulation of antiapoptotic genes after androgen deprivation. Given the accumulating evidence that Survivin, a new member of the inhibitor of apoptosis (IAP) family, is associated with both cancer progression and drug resistance, we hypothesized that Survivin plays a potentially important role in hormone therapy resistance, and that targeting of Survivin may enhance sensitivity to antiandrogen therapy in prostate cancer. Patterns of Survivin expression were assessed in three prostate cancer cell lines LNCaP, PC-3, and DU-145 using quantitative Western analysis. All three cell lines were found to strongly express Survivin. In LNCaP cells with intact androgen receptors (ARs), it was observed that androgen stimulation with 5alpha-dihydrotestosterone (DHT) increased Survivin expression. Conversely, treatment with Flutamide decreased Survivin expression in LNCaP cells. We next studied the functional effect of Survivin on sensitivity to Flutamide. LNCaP cells were infected with replication-deficient adenoviruses encoding either wild-type Survivin pAd-S(WT) or a phosphorylation-defective Survivin Thr34 --> Ala dominant-negative mutant pAd-S(T34A), and then treated with Flutamide. Cell viability and apoptosis were assessed in vitro and in vivo. It was determined that Survivin can mediate resistance to such antiandrogen therapies based on our assays. Direct androgen stimulation resulted in pan-cell cycle expression of Survivin, which was found to be mediated by AKT, as it was determined that exogenous insulin-like growth factor-1 (IGF-1), a known activator of AKT signaling, could increase Survivin expression and result in pan-cell cycle expression even in AR-negative prostate cancer cell lines PC-3 and DU-145. Given this alternative mechanism of Survivin expression and our findings that Survivin can mediate resistance to Flutamide treatment, we further investigated whether IGF-1-mediated activation of Survivin via AKT could mediate resistance to antiandrogen therapy. Both in vitro and in vivo, this was found to be the case, supporting a novel mechanism of resistance to antiandrogen therapy. Our study indicates that upregulation of Survivin via IGF-1 signaling confers resistance to Flutamide in prostate cancer cells. Targeted inhibition of Survivin appears to enhance the therapeutic effects of Flutamide in vitro and in vivo, revealing a novel strategy to enhance sensitivity to androgen ablation therapy.
The downstream effector of PI3K, Akt, is frequently hyperactivated in human cancers. A critical downstream effector of Akt, which contributes to tumorigenesis, is mTOR. In the PI3K/Akt/mTOR pathway, Akt is flanked by two tumor suppressors: PTEN, acting as a brake upstream of Akt, and TSC1/TSC2 heterodimer, acting as a brake downstream of Akt and upstream of mTOR. In the absence of the TSC1/TSC2 brake, mTOR activity is unleashed to inhibit Akt via an inhibitory feedback mechanism. Two recent studies used mouse genetics to assess the roles of PTEN and TSC2 in cancer, underscoring the importance of Akt-mTOR interplay for cancer progression and therapy.
An abundance of scientific literature exists demonstrating that oxidative stress influences the MAPK signaling pathways. This review summarizes these findings for the ERK, JNK, p38, and BMK1 pathways. For each of these different MAPK signaling pathways, the following is reviewed: the proteins involved in the signaling pathways, how oxidative stress can activate cellular signaling via these pathways, the types of oxidative stress that are known to induce activation of the different pathways, and the specific cell types in which oxidants induce MAPK responses. In addition, the functional outcome of oxidative stress-induced activation of these pathways is discussed. The purpose of this review is to provide the reader with an overall understanding and appreciation of oxidative stress-induced MAPK signaling.