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)

Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor models in vivo. While surveying the effect of flavopiridol on cell cycle progression in different cell types, we discovered that hematopoietic cell lines, including SUDHL4, SUDHL6 (B-cell lines), Jurkat, and MOLT4 (T-cell lines), and HL60 (myeloid), displayed notable sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 12 hours, SUDHL4 cells displayed a similar degree of DNA fragmentation to that shown by the apoptosis-resistant PC3 prostate carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to 1,000 nmol/L flavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells despite comparable potency (SUDHL4: 120 nmol/L; PC3: 203 nmol/L) in causing growth inhibition by 50% (IC50). Flavopiridol did not induce topoisomerase I or II cleavable complex activity. A relation of p53, bcl2, or bax protein levels to apoptosis in SUDHL4 was not appreciated. While flavopiridol caused cell cycle arrest with decline in CDK1 activity in PC3 cells, apoptosis of SUDHL4 cells occurred without evidence of cell cycle arrest. These results suggest that antiproliferative activity of flavopiridol (manifest by cell cycle arrest) may be separated in different cell types from a capacity to induce apoptosis. Cells from hematopoietic neoplasms appear in this limited sample to be very susceptible to flavopiridol-induced apoptosis and therefore clinical trials in hematopoietic neoplasms should be of high priority.
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PMID:Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. 942 98

Flavopiridol is a flavone that inhibits several cyclin-dependent kinases and exhibits potent growth-inhibitory activity against a number of human tumor cell lines, both in vitro and when grown as xenografts in mice. It is presently being investigated as a novel antineoplastic agent in the primary screen conducted by the Developmental Therapeutics Program, National Cancer Institute. Because breast cancer is the most common cancer and second leading cause of cancer-related deaths in women in the United States, we investigated whether flavopiridol could be an effective agent against a series of isogenic breast- cancer cell lines having different levels of erbB-2 expression and differential invasion and metastatic characteristics. Flavopiridol was found to inhibit the growth of MDA-MB-435 (parental) and 435.eB (stable transfectants) cells that were established by transfecting c-erbB-2 cDNA into MDA-MB-435. Induction of apoptosis was also observed in these cell lines when treated with flavopiridol, as measured by DNA laddering, PARP, and CPP32 cleavages. We also found modest up-regulation of Bax and down-regulation of Bcl-2, but there was a significant down-regulation of c-erbB-2 in flavopiridol-treated cells. Gelatin zymography showed that flavopiridol inhibits the secretion of matrix metalloproteinase (MMP; MMPs 2 and 9) in the breast cancer cells and that the inhibition of c-erbB-2 and MMPs may be responsible for the inhibition of cell invasion observed in flavopiridol-treated cells. Collectively, these molecular effects of flavopiridol, however, were found to be independent of c-erbB-2 overexpression, suggesting that flavopiridol may be effective in all breast cancer. From these results, we conclude that flavopiridol inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and inhibits invasion and, thus, may inhibit metastasis of breast cancer cells. These findings suggest that flavopiridol may be an effective chemotherapeutic or preventive agent against breast cancer.
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PMID:Induction of apoptosis and inhibition of c-erbB-2 in breast cancer cells by flavopiridol. 1065 53

Compounds that inhibit protein kinases are currently undergoing clinical evaluation for the treatment of a variety of malignancies. The kinase inhibitors flavopiridol and 7 hydroxy-staurosporine (UCN-01) were examined for their effects on B-cell chronic lymphocytic leukemia (B-CLL) cells in vitro (n = 49). Flavopiridol and UCN-01 induced concentration-dependent apoptosis of most B-CLL samples tested, with greater than 50% cell killing occurring at concentrations of less than 1 mcmol/L, and with flavopiridol displaying more potent activity than UCN-01. Flavopiridol (0.1 mcmol/L) and UCN-01 (1 mcmol/L) also induced striking decreases in the levels of the antiapoptosis proteins Mcl-1, X-linked inhibitor of apoptosis (XIAP), and BAG-1 in nearly all cases of B-CLL and of Bcl-2 in approximately half of B-CLL specimens evaluated. In contrast, expression of the proapoptotic proteins Bax and Bak was not significantly influenced by these kinase inhibitors. Flavopiridol-induced decreases in the levels of antiapoptosis proteins Mcl-1 and XIAP preceded apoptosis and were not substantially affected by the addition of caspase inhibitors to cultures. In contrast, UCN-01-stimulated decreases in antiapoptosis proteins were slower, occurred concurrently with apoptosis, and were partially prevented by caspase inhibitors. The findings suggest that flavopiridol and UCN-01 induce apoptosis of B-CLL cells through different mechanisms. The potent apoptotic activities of flavopiridol and UCN-01 against cultured B-CLL cells suggest that they may be effective as single agents in the treatment of B-CLL or for sensitizing B-CLL cells to conventional cytotoxic drugs. (Blood. 2000;96:393-397)
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PMID:Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. 1088 97

Flavopiridol is an inhibitor of several cyclin-dependent kinases, and exhibits potent growth-inhibitory activity against a number of human tumor cell lines both in vitro, and when grown as xenografts in mice. It has shown promising antineoplastic activity and is currently undergoing clinical phase II testing. Prostate cancer (PCa) remains a leading cause of morbidity and mortality among males in the United States. There are no effective treatments for hormone and/or radiation refractory PCa, suggesting that novel and newer treatment strategy may be useful in the management of PCa. Our previous study showed that flavopiridol induces cell growth inhibition and apoptosis in breast cancer cells. Here, we investigated whether flavopiridol was effective against prostate cancer cells. Flavopiridol was found to inhibit growth of PC3 prostate cancer cells. Induction of apoptosis was also observed in PC3 cells treated with flavopiridol, as measured by DNA laddering and PARP cleavage. We also found a significant down-regulation of Bcl-2 in flavopiridol-treated cells. These findings suggest that down-regulation of Bcl-2 may be one of the molecular mechanisms through which flavopiridol induces apoptosis and inhibits cell growth, suggesting that flavopiridol may be an effective chemotherapeutic agent against prostate cancer.
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PMID:Induction of growth inhibition and apoptosis in prostate cancer cells by flavopiridol. 1099 88

Flavopiridol inhibits phosphokinases. Its activity is strongest on cyclin dependent kinases (cdk-1, -2, -4, -6, -7) and less on receptor tyrosine kinases (EGFR), receptor associates tyrosine kinases (pp60 Src) and on signal transducing kinases (PKC and Erk-1). Although the inhibiting activity of flavopiridol is strongest for cdk, the cytotoxic activity of flavopiridol is not limited to cycling cells. Resting cells are also killed. This fact suggests that inhibition of cdks involved in the control of cell cycle is not the only mechanism of action. Inhibition of cdk's with additional functions (i.e. involved in the control of transcription or function of proteins that do not control cell cycle) may contribute to the antitumoral effect. Moreover, direct and indirect inhibition of receptor activation (EGFR) and/or a direct inhibition of kinases (pp60 Src, PKC, Erk-1) involved in the signal transduction pathway could play a role in the antiproliferative activity of flavopiridol. From pharmacokinetic data in patients it can be concluded that the inhibitory activity (IC50) of flavopiridol on these kinases is in the range of concentrations that might be achieved intracellularly after systemic application of non-toxic doses of flavopiridol. However, no in situ data from flavopiridol treated cells have been published yet that prove that by inhibition of EGFR, pp60 Src, PKC and/or Erk-1 (in addition to inhibition of cdk's) flavopiridol is able to induce apoptosis. Thus many questions regarding the detailed mechanism of antitumoral action of flavopiridol are still open. For the design of protocols for future clinical studies this review covers the essential information available on the mechanism of antitumoral activity of flavopiridol. The characteristics of this antitumoral activity include: High rate of apoptosis, especially in leukemic cells; synergy with the antitumoral activity of many cytostatics; independence of its efficacy on pRb, p53 and Bcl-2 expression; lack of interference with the most frequent multidrug resistance proteins (P-glycoprotein and MRP-190); and a strong antiangiogenic activity. Based on these pharmacological data it can be concluded that flavopiridol could be therapeutically active in tumor patients: independent on the genetic status of their tumors or leukemias (i.e. mutations of the pRb and/or p53, amplification of bcl-2); in spite of drug resistance of their tumors induced by first line treatment (and caused by enhanced expression of multidrug resistance proteins); in combination with conventional chemotherapeutics preferentially given prior to flavopiridol; and due to a complex mechanism involving cytotoxicity on cycling and on resting tumor cells, apoptosis and antiangiogenic activity. In consequence, flavopiridol is a highly attractive, new antitumoral compound and deserves further elucidation of its clinical potency.
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PMID:Mechanisms of action of flavopiridol. 1131 60

Flavopiridol, a synthetic flavone, is currently under clinical investigation for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL). In this study, we examined the in vitro effects of flavopiridol and fludarabine on B-CLL cells from 64 patients (36 treated and 28 untreated) in terms of apoptosis induction and Bcl-2 family expression. Both flavopiridol and fludarabine induced apoptosis in all the samples tested with mean LD(50) values (+/- SD) of 59.7 nmol/l (+/- 36.5) and 6.2 micromol/l (+/- 7.5) respectively. Mean flavopiridol LD(50) values were not significantly different between the treated and untreated patient groups (P = 0.35), whereas the fludarabine LD(50) values were significantly higher in the previously treated patient group (P = 0.01). Bcl-2 and Mcl-1 expression were downregulated in both flavopiridol and fludarabine-induced apoptotic cells, but the increase in Bax expression that accompanied fludarabine-induced apoptosis was not evident in flavopiridol-treated cells. In addition, Bcl-2:Bax ratios were not predictive of flavopiridol cytotoxicity (P = 0.82), whereas they were highly predictive of in vitro responsiveness to fludarabine (P = 0.001). Overall, these findings suggest that flavopiridol exerts its cytotoxic effect through a novel cell-death pathway that is not subject to the Bcl-2 family mediated resistance mechanisms that reduce the efficacy of many conventional chemotherapeutic drugs.
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PMID:Flavopiridol circumvents Bcl-2 family mediated inhibition of apoptosis and drug resistance in B-cell chronic lymphocytic leukaemia. 1147 47

Although myeloma shows responsiveness in intensive chemotherapy, overall survival remains less than 40% at 2 years. Since myeloma appears to be dependent on cytokines, such as IL-6, we hypothesized that targeting signal transduction molecules could effectively treat myeloma. Two myeloma cell lines U266 and RPMI-8226 and CD38+ myeloma cells were studied by immune complex kinase assay or anti-phosphotyrosine blot for evidence of constitutive activation of tyrosine kinases. Growth arrest and apoptosis were evaluated in these two cell lines following their treatment with specific kinase inhibitors. We found that a variety of Src and Janus kinases were present and constitutively active in U266 and RPMI-8226 cells. Inhibitors of both Src and Janus kinases were inferior to the cyclin-dependent kinase inhibitor, flavopiridol, in inducing both growth arrest with GI50 of 100 nM and apoptosis in both cell lines and CD38+ myeloma cells. Although, flavopiridol did not affect cyclin D1 and cyclin A levels, it inhibited Mcl-1 and Bcl-2 protein levels and cyclin-dependent kinase 2 activity. Flavopiridol is a well-tolerated drug, currently in phase I-II trials for a variety of tumors. A clinical trial using flavopiridol should be performed in patients with myeloma. Its mechanism of action may involve targets other than the cyclin-dependent kinases.
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PMID:Growth inhibition and apoptosis of myeloma cells by the CDK inhibitor flavopiridol. 1179 16

Flavopiridol is a synthetic flavone that inhibits tumor growth by suppressing cyclin-dependent kinases (CDKs). We have investigated effects of flavopiridol in oral squamous cell carcinoma (OSCC). Flavopiridol was found to inhibit the growth of OSCC cells in a time- and dose-dependent manner. Induction of apoptosis was observed in all cells showing accumulated cells with sub-G(1) DNA contents, DNA fragmentations, and PARP cleavages. While Bcl-2 and Bax expression did not change, Bcl-x(L) was down regulated and Bcl-xs was up-regulated after being exposed to flavopiridol. Flavopiridol treatments also resulted in remarkable reductions of cyclin A, cyclin B, and cyclin D1 expressions. We also found that expression levels of CDK activation kinase and CDC25C were reduced, and p34 inactive form CDK2 were up-regulated. Our data indicate that flavopiridol has growth inhibition activities against OSCC. Flavopiridol not only inhibits CDKs directly, but it also inhibits the CDKs activation pathway and activates the Bcl-x apoptotic pathway.
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PMID:Flavopiridol, a cyclin dependent kinase (CDK) inhibitor, induces apoptosis by regulating Bcl-x in oral cancer cells. 1245 21

Flavopiridol is a synthetic flavone, which inhibits growth in vitro and in vivo of several solid malignancies such as renal, prostate, and colon cancers. It is a potent cyclin-dependent kinase inhibitor presently in clinical trials. In this study, we examined the effect of flavopiridol on a panel of glioma cell lines having different genetic profiles: five of six have codeletion of p16(INK4a) and p14(ARF); three of six have p53 mutations; and one of six shows overexpression of mouse double minute-2 (MDM2) protein. Independent of retinoblastoma and p53 tumor suppressor pathway alterations, flavopiridol induced apoptosis in all cell lines but through a caspase-independent mechanism. No cleavage products for caspase 3 or its substrate poly(ADP-ribose) polymerase or caspase 8 were detected. The pan-caspase inhibitor Z-VAD-fmk did not inhibit flavopiridol-induced apoptosis. Mitochondrial damage measured by cytochrome c release and transmission electron microscopy was not observed in drug-treated glioma cells. In contrast, flavopiridol treatment induced translocation of apoptosis-inducing factor from the mitochondria to the nucleus. The proteins cyclin D(1) and MDM2 involved in the regulation of retinoblastoma and p53 activity, respectively, were down-regulated early after flavopiridol treatment. Given that MDM2 protein can confer oncogenic properties under certain circumstances, loss of MDM2 expression in tumor cells could promote increased chemosensitivity. After drug treatment, a low Bcl-2/Bax ratio was observed, a condition that may favor apoptosis. Taken together, the data indicate that flavopiridol has activity against glioma cell lines in vitro and should be considered for clinical development in the treatment of glioblastoma multiforme.
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PMID:Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway. 1258 31

Flavopiridol, a synthetic flavone, has been previously shown to induce apoptosis in B-cell chronic lymphocytic leukaemia (B-CLL) cells in vitro. The apoptosis was associated with a concomitant activation of caspase-3 without evidence of dependence on functional p53 or Bcl-2 family modulation. In this study, we examined flavopiridol-induced apoptosis in terms of upstream caspase activity, cell cycle distribution and signal transduction, in order to elucidate the mechanism of action of this potent cytotoxic agent. Flavopiridol-induced apoptosis was significantly abrogated by the caspase-9 inhibitor Z-LEHD-FMK (p = 0.002; paired t-test) but was not altered by the caspase-8 inhibitor Z-IETD-FMK (p = 0.37; paired t-test). There was a concentration-dependent increase in a sub G0/G1 peak indicative of apoptotic cells but if these cells were excluded by gating no other cell cycle perturbations were observed suggesting that flavopiridol is capable of inducing apoptosis in cells in all phases of the cell cycle. Significantly, apoptosis was associated with activation of p38 MAP kinase and suppression of ERK activity (p = 0.0036 and p = 0.0048, respectively; paired t-test). These results show for the first time that flavopiridol modulates specific cellular signal transduction pathways in B-CLL cells thereby altering the balance between survival and cell death signals and providing a rationale for the p53-independent nature of flavopiridol-induced apoptosis. Further work is required to identify whether combinations of conventional chemotherapeutic drugs and novel agents like flavopiridol can be used to improve patient outcomes in the treatment of B-CLL.
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PMID:Flavopiridol induces apoptosis in B-cell chronic lymphocytic leukaemia cells through a p38 and ERK MAP kinase-dependent mechanism. 1268 54


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