Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

Resveratrol (R-3), a trihydroxy trans-stilbene from grape, inhibits multistage carcinogenesis in animal models. A resveratrol derivative 3,4,5,4'-tetrahydroxystilbene (R-4) exhibits potent growth inhibitory effect against transformed human cells. Here we report that 3,4,5,4'-tetramethoxystilbene (MR-4), converted from R-4, was more potent against cancer cell lines (WI38VA, IMR-90SV, HeLa, LNCaP, HT-29, and HepG2), but had almost no inhibitory effect on the growth of normal cells (WI38, IMR-90, BJ-T) at the concentrations tested. The IC50 value of MR-4 on the growth inhibition of transformed WI38VA human cells was 0.5 microM, as compared to the value of greater than 50 microM for the normal WI38 cells. Resveratrol, however, did not exhibit such clear differential effect and the IC50 value of R-3 for WI38VA cells was about 50 microM. The growth inhibitory effect of MR-4 correlated with the induction of apoptosis in the transformed cells. When normal WI38 cells and transformed WI38VA cells were compared, MR-4 induced increases of the Bax/Bcl-2 mRNA ratio, p53 and Bax protein level, activation of caspases, and DNA fragmentation in transformed, but not in normal cells. Further analysis revealed that MR-4 caused a rapid appearance of perinuclear aggregation of mitochondria in WI38VA but not in WI38 cells, suggesting that the mitochondria could serve as an early target of MR-4. R-3 also induced apoptosis and mitochondrial clustering but only at a much higher concentration, close to 500 microM. Taken together, the specific activation of the mitochondria-mediated apoptotic pathway could be a major reason for the striking differential growth inhibitory effect of MR-4.
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PMID:A methoxy derivative of resveratrol analogue selectively induced activation of the mitochondrial apoptotic pathway in transformed fibroblasts. 1566 17

Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERaalpha)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kappaB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kappaB, were both inhibited by RES. The patterns for NF-kappaB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kappaB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kappaB and calpain protease activity. Therefore, Bcl-2 and NF-kappaB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells.
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PMID:Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB. 1568 15

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a naturally occurring phytoalexin found in grapes and wine, and has been reported to exert a variety of important pharmacological effects. We have investigated the activity of resveratrol on proliferation and differentiation of the acute promyelocytic leukemia cell line NB4. The growth inhibitory properties of resveratrol appear to be due to its induction of apoptotic cell death, as determined by morphological changes, DNA fragmentation, increased proportion of the subdiploid cell population and decreased mitochondrial transmembrane potential (Deltapsi(m)). Colorimetric assay for activity of caspase-3 showed an obvious increase in caspase-3 activity in cells after treatment with resveratrol. However, the expression levels of protein Bcl-2 and Bax show no significant change in response to resveratrol treatment. These results suggest that apoptosis of NB4 cells induced by resveratrol requires caspase-3 activation and is related to the mitochondrial transmembrane potential. The combination of resveratrol and all-tran-retinoic acid (ATRA) induced 100% of the NB4 cells to become NBT-positive, whereas only a small part of cells became positive for NBT after a similar exposure to either resveratrol or ATRA alone. Thus, resveratrol may be useful in treating acute promyelocytic leukemia.
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PMID:Resveratrol induces apoptosis and differentiation in acute promyelocytic leukemia (NB4) cells. 1608 38

Resveratrol has been proposed to act as a chemopreventive agent in numerous epidemiologic studies and has been shown to inhibit proliferation of various tumor cells in vitro. In the present study, we investigated the antitumor effects of resveratrol on multiple myeloma (MM) cells and the mechanisms involved. Our findings indicated that resveratrol inhibited proliferation of tumor cells in a dose- [corrected] dependent manner by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and [3H]thymidine incorporation assay. Resveratrol also enhanced the inhibitory effect of dexamethasone on the growth of MM cells by MTT assay. Flow cytometric analysis demonstrated that resveratrol arrested the cells at the G1 and S phases of the cell cycle. Because nuclear factor-kappaB (NF-kappaB) plays a key role in cell survival and proliferation of human MM cells, we tested the effect of resveratrol on NF-kappaB expression by Western blot analysis and immunofluorescence. NF-kappaB was constitutively active in all human MM cell lines examined, and resveratrol down-regulated NF-kappaB expression in all cell lines. Resveratrol also down-regulated the expression of NF-kappaB-regulated gene products by Western blot analysis, gelatin zymography, and enzyme-linked immunosorbent assay, including interleukin-6, Bcl-2, Bcl-xL, XIAP, c-IAP, vascular endothelial growth factor (VEGF), and matrix metalloproteinase-9 (MMP-9), which modulates an array of signals controlling cellular survival and proliferation and tumor promotion. Indeed, annexin V-fluoroisothyocyanate and Transwell invasion analyses revealed that incubation of MM cells with resveratrol resulted in apoptotic cell death and inhibition of invasion. In conclusion, these data suggest that resveratrol is an effective in vitro inhibitor of NF-kappaB in human MM cells. Resveratrol plays a role in suppressing the proliferation of MM cells and induces apoptosis, thus providing the molecular basis for the treatment of MM patients with this compound.
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PMID:Resveratrol downregulates the constitutional activation of nuclear factor-kappaB in multiple myeloma cells, leading to suppression of proliferation and invasion, arrest of cell cycle, and induction of apoptosis. 1649 May 92

Prostate cancer is a major health problem in the U.S. and the available treatment and surgical options have proven to be inadequate in controlling the mortality and morbidity associated with this disease. It is therefore necessary to intensify our efforts to better understand this disease and develop novel approaches for its prevention and treatment. This study was conducted to evaluate the chemopreventive/antiproliferative potential of resveratrol (trans-3,4',5,-trihydroxystilbene) against prostate cancer and its mechanism of action. Treatment with resveratrol (0-50 micromol/L for 24 hours) resulted in a significant (a) decrease in cell viability, (b) decrease of clonogenic cell survival, (c) inhibition of androgen (R1881)-stimulated growth, and (d) induction of apoptosis in androgen-responsive human prostate carcinoma (LNCaP) cells. Interestingly, at similar concentrations, resveratrol treatment did not affect the viability or rate of apoptosis in normal human prostate epithelial cells. Furthermore, our data showed that resveratrol-treatment resulted in significant dose-dependent inhibition in the constitutive expression of phosphatidylinositol 3'-kinase and phosphorylated (active) Akt in LNCaP cells. Resveratrol treatment for LNCaP cells was also found to result in a significant (a) loss of mitochondrial membrane potential, (b) inhibition in the protein level of antiapoptotic Bcl-2, and (c) increase in proapoptotic members of the Bcl-2 family, i.e., Bax, Bak, Bid, and Bad. Taken together, our data suggested that resveratrol causes an inhibition of phosphatidylinositol 3'-kinase/Akt activation that, in turn, results in modulations in Bcl-2 family proteins in such a way that the apoptosis of LNCaP cells is promoted. Based on these studies, we suggest that resveratrol could be developed as an agent for the management of prostate cancer.
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PMID:Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3'-kinase/Akt pathway and Bcl-2 family proteins. 1673 67

Whether resveratrol, a component of red grapes, berries, and peanuts, could suppress the proliferation of multiple myeloma (MM) cells by interfering with NF-kappaB and STAT3 pathways, was investigated. Resveratrol inhibited the proliferation of human multiple myeloma cell lines regardless of whether they were sensitive or resistant to the conventional chemotherapy agents. This stilbene also potentiated the apoptotic effects of bortezomib and thalidomide. Resveratrol induced apoptosis as indicated by accumulation of sub-G(1) population, increase in Bax release, and activation of caspase-3. This correlated with down-regulation of various proliferative and antiapoptotic gene products, including cyclin D1, cIAP-2, XIAP, survivin, Bcl-2, Bcl-xL, Bfl-1/A1, and TRAF2. In addition, resveratrol down-regulated the constitutive activation of AKT. These effects of resveratrol are mediated through suppression of constitutively active NF-kappaB through inhibition of IkappaBalpha kinase and the phosphorylation of IkappaBalpha and of p65. Resveratrol inhibited both the constitutive and the interleukin 6-induced activation of STAT3. When we examined CD138(+) plasma cells from patients with MM, resveratrol inhibited constitutive activation of both NF-kappaB and STAT3, leading to down-regulation of cell proliferation and potentiation of apoptosis induced by bortezomib and thalidomide. These mechanistic findings suggest that resveratrol may have a potential in the treatment of multiple myeloma.
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PMID:Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. 1716 50

Resveratrol, a polyphenol found in numerous plant species, including mulberries, peanuts and grapes, has shown to possess chemopreventive properties against several cancers, and cardiovascular diseases. Recently, resveratrol has been shown to have positive effects on age longevity, lipid levels and a preventative quality against certain cancers and viral infections. Resveratrol induces apoptosis by up-regulating the expression of Bax, Bak, PUMA, Noxa, Bim, p53, TRAIL, TRAIL-R1/DR4 and TRAIL-R2/DR5 and simultaneously down-regulating the expression of Bcl-2, Bcl-XL, Mcl-1 and survivin. Resveratrol causes growth arrest at G1 and G1/S phases of cell cycle by inducing the expression of CDK inhibitors p21/WAF1/CIP1 and p27/KIP1. Resveratrol has also been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase-2 activity, and nuclear factor-kappaB activity. Modulation of cell signaling pathway by resveratrol explains its diverse bioactivities related with human health. Resveratrol also potentiates the apoptotic effects of cytokines, chemotherapeutic agents and gamma-radiation. Pharmacokinetic and pharmacodynamic studies demonstrated that the main target organs of resveratrol are liver and kidney, and it is metabolized by hydroxylation, glucuronidation, sulfation and hydrogenation. As a chemoprevention agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression. There is growing evidence that resveratrol can prevent or delay the onset of various cancers, heart diseases, ischemic and chemically induced injuries, pathological inflammation and viral infections. This review summarizes the molecular mechanisms of resveratrol and its clinical benefits for human diseases.
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PMID:Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. 1756 14

Dopamine (DA) is an oxidant that may contribute to the degeneration of dopaminergic neurons. The present study demonstrates that DA-induced cytotoxicity in human-derived neurotypic cells, SH-SY5Y, is prevented by resveratrol, one of the major antioxidative constituents found in the skin of grapes. SH-SY5Y cells, a neuroblastoma cell line, treated with DA at 300 and 500 microM for 24 h underwent apoptotic death as determined by characteristic morphological features, including nuclear condensation, and loss of mitochondrial membrane potential (MMP). Flow cytometric analysis using Annexin V showed that DA can induce significant and severe apoptosis. Exposure to resveratrol (5 microM) for 1 h prior to the DA treatment attenuated DA-induced cytotoxicity, and rescued the loss of MMP. To investigate the apoptotic signaling pathways relevant to the restoration of DA-induced apoptosis by resveratrol, we carried out quantitative analysis of Bcl-2, caspase-3, and cleaved poly ADP-ribose polymerase (PARP) by immunoblot analysis. Resveratrol pretreatment led to a decrease in cleavage of PARP, an increase in the Bcl-2 protein, and activation of caspase-3. These results suggest that DA may be a potential oxidant of neuronal cells at biologically relevant concentrations. Resveratrol may protect SH-SY5Y cells against this cytotoxicity, reducing intracellular oxidative stress through canonical signal pathways of apoptosis and may be of biological importance in the prevention of a dopaminergic neurodegenerative disorder such as Parkinson disease.
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PMID:Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine. 1760 92

Although resveratrol, an active ingredient derived from grapes and red wine, possesses chemopreventive properties against several cancers, the molecular mechanisms by which it inhibits cell growth and induces apoptosis have not been clearly understood. Here, we examined the molecular mechanisms of resveratrol and its interactive effects with TRAIL on apoptosis in prostate cancer PC-3 and DU-145 cells. Resveratrol inhibited cell viability and colony formation, and induced apoptosis in prostate cancer cells. Resveratrol downregulated the expression of Bcl-2, Bcl-X(L) and survivin and upregulated the expression of Bax, Bak, PUMA, Noxa, and Bim, and death receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Treatment of prostate cancer cells with resveratrol resulted in generation of reactive oxygen species (ROS), translocation of Bax to mitochondria and subsequent drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO, and AIF) to cytosol, activation of effector caspase-3 and caspase-9, and induction of apoptosis. Resveratrol-induced ROS production, caspase-3 activity and apoptosis were inhibited by N-acetylcysteine. Bax was a major proapoptotic gene mediating the effects of resveratrol as Bax siRNA inhibited resveratrol-induced apoptosis. Resveratrol enhanced the apoptosis-inducing potential of TRAIL, and these effects were inhibited by either dominant negative FADD or caspase-8 siRNA. The combination of resveratrol and TRAIL enhanced the mitochondrial dysfunctions during apoptosis. These properties of resveratrol strongly suggest that it could be used either alone or in combination with TRAIL for the prevention and/or treatment of prostate cancer.
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PMID:Molecular mechanisms of resveratrol (3,4,5-trihydroxy-trans-stilbene) and its interaction with TNF-related apoptosis inducing ligand (TRAIL) in androgen-insensitive prostate cancer cells. 1763 62


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