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, a triphenolic stilbene present in grapes and other plants, has striking antioxidant and anti-inflammatory activities which have been considered to be responsible for the beneficial effects of red wine consumption on coronary heart disease. Recent studies reveal that resveratrol can inhibit each step of multistage carcinogenesis. However, the molecular mechanisms underlying anti-tumorigenic or chemopreventive activities of this phytochemical remain largely unknown. In the present work, we have found that resveratrol reduces viability and DNA synthesis capability of cultured human promyelocytic leukemia (HL-60) cells. The growth inhibitory and antiproliferative properties of resveratrol appear to be attributable to its induction of apoptotic cell death as determined by morphological and ultrastructural changes, internucleosomal DNA fragmentation, and increased proportion of the subdiploid cell population. Resveratrol treatment resulted in a gradual decrease in the expression of anti-apoptotic Bcl-2. These results, together with previous findings, suggest the cancer therapeutic as well as chemopreventive potential of resveratrol.
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PMID:Resveratrol, an antioxidant present in red wine, induces apoptosis in human promyelocytic leukemia (HL-60) cells. 1040 35

Resveratrol has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. In the present study, we determined the effect of high intracellular levels of the anti-apoptosis protein Bcl-2 on caspase-3 activation, PLC-gamma1 degradation and cytochrome c release during resveratrol-induced apoptosis. For this, we used U937/vector and U937/Bcl-2 cells, which were generated by transfection of the cDNA of the Bcl-2 gene. As compared with U937/vector, U937/Bcl-2 cells exhibited a 4-fold greater expression of Bcl-2. Treatment with 60 or 100 microM resveratrol for 24 h produced morphological features of apoptosis and DNA fragmentation in U937/vector cells, respectively. This was associated with caspase-3 activation and PLC-gamma1 degradation. In contrast, resveratrol-induced caspase-3 activation and PLC-gamma1 degradation and apoptosis were significantly inhibited in U937/Bcl-2 cells. Bcl-2 overexpressing cells exhibited less cytochrome c release and sustained expression levels of the IAP proteins during resveratrol-induced apoptosis. In addition, these findings indicate that Bcl-2 inhibits resveratrol-induced apoptosis by a mechanism that interferes with cytochrome c release and activity of caspase-3 that is involved in the execution of apoptosis.
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PMID:Bcl-2 overexpression attenuates resveratrol-induced apoptosis in U937 cells by inhibition of caspase-3 activity. 1157 2

Trans-resveratrol was analysed for its apoptotic and growth inhibitory activity in human B-cell lines derived from chronic B-cell malignancies (WSU-CLL and ESKOL), and in leukaemic lymphocytes from patients with B-cell chronic lymphocytic leukaemia (B-CLL). Resveratrol displayed antiproliferative activity on both B-cell lines, as estimated by the decrease in cell recovery and inhibition of thymidine uptake. Furthermore, resveratrol induced apoptosis in the two cell lines as well as in B-CLL patients' cells, as evidenced by the increase in annexin V binding, caspase activation, DNA fragmentation and decrease of the mitochondrial transmembrane potential DeltaPsim. We previously reported that nitric oxide (NO), endogenously released by an iNO synthase (iNOS) spontaneously expressed in these leukaemic cells, contributed to their resistance towards apoptosis. We show here that resveratrol inhibited both iNOS protein expression and in situ NO release in WSU-CLL, ESKOL and B-CLL patients'cells. In addition, Bcl-2 expression was also inhibited by resveratrol. Thus, downregulation of the two anti-apoptotic proteins iNOS and Bcl-2 can contribute to the apoptotic effects of resveratrol in leukaemic B cells from chronic leukaemia. Our data suggest that this drug is of potential interest for the therapy of B-CLL.
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PMID:Analysis of resveratrol-induced apoptosis in human B-cell chronic leukaemia. 1206 Jan 19

trans-Resveratrol (3,4',5-trihydroxystilbene) is able to significantly reduce paclitaxel-induced apoptosis in the human neuroblastoma (HN) SH-SY5Y cell line, acting on several cellular signaling pathways that are involved in paclitaxel-induced apoptosis. trans-Resveratrol reverses phosphorylation of Bcl-2 induced by paclitaxel and concomitantly blocks Raf-1 phosphorylation, also observed after paclitaxel exposure, thus suggesting that Bcl-2 inactivation may be dependent on the activation of the Raf/Ras cascade. trans-Resveratrol also reverses the sustained phosphorylation of JNK/SAPK, which specifically occurs after paclitaxel exposure.Overall, our observations demonstrate that (a) the toxic action of paclitaxel on neuronal-like cells is not only related to the effect of the drug on tubulin, but also to its capacity to activate several intracellular pathways leading to inactivation of Bcl-2, thus causing cells to die by apoptosis, (b) trans-resveratrol significantly reduces paclitaxel-induced apoptosis by modulating the cellular signaling pathways which commit the cell to apoptosis.
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PMID:Effect of trans-resveratrol on signal transduction pathways involved in paclitaxel-induced apoptosis in human neuroblastoma SH-SY5Y cells. 1251 25

Resveratrol (3,4',5-trihydroxystilbene) is a phytoalexin found in grapes and other food products that can prevent cancer. We studied the in vitro biological activity of this compound by examining its effect on proliferation and inducing apoptosis in three lung cancer cell lines (A549, EBC-1, Lu65). Resveratrol inhibited the growth of A549, EBC-1 and Lu65 lung cancer cells by 50% (ED50) at concentrations between 5-10 microM. We also examined the combined effects in these cells of resveratrol and paclitaxel, an essential chemotherapeutic agent against lung cancer. Although simultaneous exposure to resveratrol plus paclitaxel did not result in significant synergy, resveratrol (10 microM, 3 days) significantly enhanced the subsequent antiproliferative effect of paclitaxel. In addition, resveratrol as well as paclitaxel induced apoptosis in EBC-1 and Lu65 cells, as measured by TUNEL and caspase assays, as well as flow cytometry. Resveratrol (10 microM, 3 days) similarly enhanced the subsequent apoptotic effects of paclitaxel. We examined the effects of resveratrol and paclitaxel on levels of p21waf1, p27kip1, E-cadherin, EGFR and Bcl-2 in EBC-1 cells. Resveratrol (10 microM, 3 days) prior to paclitaxel induced p21waf1 expression approximately 4-fold. These results suggest that resveratrol may be a promising alternative therapy for lung cancer and that lung cancer cells exposed to resveratrol have a lowered threshold for killing by paclitaxel.
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PMID:Combined effects of resveratrol and paclitaxel on lung cancer cells. 1466 16

Resveratrol, which is found in grapes and wine, has been reported to have a variety of important pharmacological effects including anti-inflammatory, anti-platelet, and anti-carcinogenetic properties. In this study, using the human breast cancer cell line MCF-7, we have analyzed a possible mechanism by which resveratrol could interfere with cell cycle control and induce cell death. Resveratrol treatment of MCF-7 cells resulted in a dose-dependent inhibition of the cell growth and the cells accumulated at the S phase transition of the cell cycle at low concentrations, but high concentrations do not induce S phase accumulation. The anti-proliferative effects of resveratrol were associated with a marked inhibition of cyclin D and cyclin-dependent kinase (Cdk) 4 proteins, and induction of p53 and Cdk inhibitor p21WAF1/CIP. Growth suppression by resveratrol was also due to apoptosis, as seen by the appearance of a sub-G1 fraction and chromatin condensation. In addition, the apoptotic process involves activation of caspase-9, a decrease of Bcl-2 as well as Bcl-XL levels, and an increase of Bax levels.
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PMID:Resveratrol inhibits cell proliferation and induces apoptosis of human breast carcinoma MCF-7 cells. 1471 81

Resveratrol (3,5,4-trihydroxystilbene), a natural phytoalexin present in grapes, nuts, and red wine, has antineoplastic activities. Several molecular mechanisms have been described to underlie its effects on cells in vitro and in vivo. In the present study, the response of ovarian cancer cells to resveratrol is explored. Resveratrol inhibited growth and induced death in a panel of five human ovarian carcinoma cell lines. The response was associated with mitochondrial release of cytochrome c, formation of the apoptosome complex, and caspase activation. Surprisingly, even with these molecular features of apoptosis, analysis of resveratrol-treated cells by light and electron microscopy revealed morphology and ultrastructural changes indicative of autophagocytic, rather than apoptotic, death. This suggests that resveratrol can induce cell death through two distinct pathways. Consistent with resveratrol's ability to kill cells via nonapoptotic processes, cells transfected to express high levels of the antiapoptotic proteins Bcl-x(L) and Bcl-2 are equally sensitive as control cells to resveratrol. Together, these findings show that resveratrol induces cell death in ovarian cancer cells through a mechanism distinct from apoptosis, therefore suggesting that it may provide leverage to treat ovarian cancer that is chemoresistant on the basis of ineffective apoptosis.
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PMID:Resveratrol-induced autophagocytosis in ovarian cancer cells. 1474 87

Resveratrol, a polyphenolic phytoalexin found in grapes, may have potential for the prevention and treatment of human cancer. We report here that resveratrol inhibits the growth of human prostate carcinoma DU145 cells and provide a molecular explanation of the effect. Resveratrol treatment in DU145 cells resulted in a dose-dependent inhibition of cell growth and induced apoptotic cell death. The antiproliferative effect of resveratrol was associated with the inhibition of D-type cyclins and cyclin-dependent kinase (Cdk) 4 expression, and the induction of tumor suppressor p53 and Cdk inhibitor p21. Moreover, the kinase activities of cyclin E and Cdk2 were inhibited by resveratrol without alteration of their protein levels. Resveratrol treatment also up-regulated the Bax protein and mRNA expression in a dose-dependent manner; however, Bcl-2 and Bcl-xL levels were not significantly affected. These effects were found to correlate with an activation of caspase-3 and caspase-9. Taken together, our study suggests that resveratrol has a strong potential for development as an agent for the prevention of human prostate cancer.
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PMID:Antiproliferative effect of resveratrol in human prostate carcinoma cells. 1497 34

Recent studies demonstrated that resveratrol, a grape-derived polyphenolic phytoalexin, provides pharmacological preconditioning (PC) of the heart through a NO-dependent mechanism. Because adenosine receptors play a role in PC, we examined whether they play any role in resveratrol PC. Rats were randomly assigned to groups perfused for 15 min with 1) Krebs-Henseleit bicarbonate buffer (KHB) only; 2) KHB containing 10 microM resveratrol; 3) 10 microM resveratrol + 1 microM 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A(1) receptor blocker); 4) 10 microM resveratrol + 1 microM 8-(3-chlorostyryl)caffeine (CSC; adenosine A(2a) receptor blocker); 5) 10 microM resveratrol + 1 microM 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; adenosine A(3) receptor blocker); or 6) 10 microM resveratrol + 3 microM 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride [LY-294002, phosphatidylinositol (PI)3-kinase inhibitor], and groups perfused with adenosine receptor blockers alone. Hearts were then subjected to 30-min ischemia followed by 2-h reperfusion. The results demonstrated significant cardioprotection with resveratrol evidenced by improved ventricular recovery and reduced infarct size and cardiomyocyte apoptosis. CPT and MRS 1191, but not CSC, abrogated the cardioprotective abilities of resveratrol, suggesting a role of adenosine A(1) and A(3) receptors in resveratrol PC. Resveratrol induced expression of Bcl-2 and caused its phosphorylation along with phosphorylation of cAMP response element-binding protein (CREB), Akt, and Bad. CPT blocked phosphorylation of Akt and Bad without affecting CREB, whereas MRS 1191 blocked phosphorylation of all compounds, including CREB. LY-294002 partially blocked the cardioprotective abilities of resveratrol. The results indicate that resveratrol preconditions the heart through activation of adenosine A(1) and A(3) receptors, the former transmitting a survival signal through PI3-kinase-Akt-Bcl-2 signaling pathway and the latter protecting the heart through a CREB-dependent Bcl-2 pathway in addition to an Akt-Bcl-2 pathway.
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PMID:Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation. 1534 77

The natural phytoalexin resveratrol (3, 5, 4'-trihydroxystilbene) exhibits both chemopreventive and antitumor activities through a variety of mechanisms. We have shown previously that resveratrol-induced apoptosis of a human colon cancer cell line involved the redistribution of CD95 (Fas/Apo-1) into lipid rafts. Here, we show that, in colon cancer cells that resist to resveratrol-induced apoptosis, the polyphenol also induces a redistribution of death receptors into lipid rafts. This effect sensitizes these tumor cells to death receptor-mediated apoptosis. In resveratrol-treated cells, tumor necrosis factor (TNF), anti-CD95 antibodies and TNF-related apoptosis-inducing ligand (TRAIL) activate a caspase-dependent death pathway that escapes Bcl-2-mediated inhibition. Resveratrol does not enhance the number of death receptors at the surface of tumor cells but induces their redistribution into lipid rafts and facilitates the caspase cascade activation in response to death receptor stimulation. The cholesterol sequestering agent nystatin prevents resveratrol-induced death receptor redistribution and cell sensitization to death receptor stimulation. Thus, whatever its ability to induce apoptosis in a tumor cell, resveratrol induces redistribution of death receptors into lipid rafts. This redistribution sensitizes the cells to death receptor stimulation. Such a sensitizing effect may be of therapeutic interest if TRAIL agonists are introduced in clinics.
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PMID:Redistribution of CD95, DR4 and DR5 in rafts accounts for the synergistic toxicity of resveratrol and death receptor ligands in colon carcinoma cells. 1548 Apr 30


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