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)

Anti-Fas monoclonal antibody (mAb) kills Fas-expressing cells by apoptosis. Several anticancer agents also mediate apoptosis and may share common intracellular pathways leading to apoptosis with Fas. Thus, we reasoned that combination treatment of drug-resistant cells with anti-Fas mAb and drugs might overcome their resistance. We investigated whether anticancer agents enhance Fas-mediated apoptosis and cytotoxicity against renal cell carcinoma (RCC) cells. Treatment of ACHN RCC cells with anti-Fas mAb in combination with 5-fluorouracil, vinblastine, IFN-alpha, or IFN-gamma did not overcome resistance to these agents. However, combination treatment with anti-Fas mAb and Adriamycin (ADR) resulted in a synergistic cytotoxic effect. Furthermore, synergy was also obtained even when the exposure time was shortened from 24 h to 8 or 2 h. Synergy was also achieved in four other RCC cell lines and five freshly derived human RCC cells. Treatment with anti-Fas mAb in combination with epirubicin or pirarubicin also resulted in a synergistic cytotoxic effect on ACHN cells. Similar results were achieved with a combination of humanized anti-Fas mAb and ADR. Incubation of ACHN cells with ADR augmented the expression of Fas and p53, but not Bcl-2, Bax, or caspase-3. However, the activity of caspase-3 itself was apparently enhanced after treatment with ADR alone or combined treatment with anti-Fas mAb. The synergy obtained in cytotoxicity with anti-Fas mAb and ADR was also achieved in apoptosis. Exposure of ACHN cells and freshly derived RCC cells to ADR enhanced their susceptibility to lysis by peripheral blood lymphocytes and tumor-infiltrating lymphocytes. This study demonstrates that combination treatment of RCC cells with anti-Fas mAb and ADR might overcome their resistance. The sensitization required a low concentration of ADR and a short exposure time, thus supporting the potential in vivo application of a combination of ADR and anti-Fas mAb or immunotherapy in the treatment of ADR- and/or immunotherapy-resistant RCC.
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PMID:Enhancement of Fas-mediated apoptosis in renal cell carcinoma cells by adriamycin. 1085 Apr 37

Sodium butyrate (NaBt), one of the short chain fatty acids naturally formed in the gastrointestinal tract, induces differentiation as well as apoptosis in numerous cell types. The objectives of this study were to characterize the effects of NaBt on the growth, cell cycle, and apoptosis of human renal cell carcinoma (RCC) cells, and to determine whether NaBt enhances the Fas-mediated cytotoxicity in these cells. NaBt reduced the in vitro growth rate of human RCC ACHN cells in a time- and dose-dependent manner. Treatment of ACHN cells with 1 mM NaBt resulted in G1 cell cycle arrest, accompanied by up-regulation of p21 (waf1/cip1) and down-regulation of cyclin D1. In contrast, 5 mM NaBt-induced apoptotic cell death in ACHN cells, accompanied by up-regulation of BaK and down-regulation of Bcl-2. Furthermore, NaBt synergistically enhanced the growth-inhibitory effect of anti-Fas monoclonal antibody, CH11 on CH11-sensitive ACHN cells, and apoptotic cell death was induced by the combination of sublethal doses of NaBt and CH11, but not by either agent alone. Similar synergy was also observed in CH11-resistant human RCC KN39 cells. These findings suggest that NaBt could be a novel attractive approach for patients with RCC, and that the efficacy of NaBt may be enhanced by the combined use of Fas-mediated therapy.
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PMID:Sodium butyrate induces apoptosis in human renal cell carcinoma cells and synergistically enhances their sensitivity to anti-Fas-mediated cytotoxicity. 1107 7

Objectives. To characterize the synergistic antitumor effects of the calcium ionophore, ionomycin, and of cisplatin against human renal cell carcinoma cell line, ACHN, both in vitro and in vivo.Methods. The in vitro growth rate of ACHN after exposure to these compounds was measured, using the MTT assay. The apoptotic features in ACHN were evaluated by DNA ladder analysis and flow cytometric analysis. Bcl-2 and Bax expression levels in ACHN after treatment were examined by Western blot. The synergistic antitumor effects of ionomycin and cisplatin against the growth of established ACHN tumors in athymic nude mice were then tested.Results. The in vitro growth rate of ACHN was suppressed more by ionomycin and cisplatin in combination than by either alone. DNA ladder and fragmentation were more obvious when the cells were incubated with ionomycin and cisplatin together than with either reagent alone. Ionomycin treatment increased the expression level of Bax protein, whereas Bcl-2 expression was not influenced. Although an intraperitoneal injection of cisplatin or an intratumoral injection of ionomycin against subcutaneous ACHN tumors somewhat reduced tumorigenicity in nude mice, the effect was significantly enhanced by a combination of these drugs.Conclusions. The synergistic antitumor effects suggest that ionomycin-based therapy could be a novel therapeutic strategy with which to treat advanced renal cell carcinoma.
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PMID:Synergistic antitumor effect of ionomycin and cisplatin against renal cell carcinoma in vitro and in vivo. 1116 79

Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we demonstrate that monensin inhibited the proliferation of renal cell carcinoma cells with IC50 of about 2.5 micro M. Monensin induced a G1 or a G2-M phase arrest in these cells. When we examined the effects of this drug on ACHN cells, monensin decreased the levels of CDK2, CDK6, cdc2, cyclin A and cyclin B1 proteins. p21 and p27 proteins were increased by monensin. In addition, monensin markedly enhanced the binding of p21 with CDK2 and the binding of p27 with CDK6. Furthermore, the activities of CDK2- and CDK6-associated kinase were reduced in association with hypophosphorylation of Rb protein. Monensin also induced the apoptosis in several renal cell carcinoma cells. Apoptotic process of Caki-2 cells was associated with the changes of Bcl-2, Bcl-XL, caspase-9, caspase-3, caspase-7 proteins as well as mitochondria transmembrane potential (DeltaPsim) loss. Taken together, these results demonstrate for the first time that monensin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis.
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PMID:Monensin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis. 1263 79

We investigated the in vitro effect of trichostatin (histone deacetylase inhibitor) on cell proliferation, cell cycle regulation and apoptosis in renal cell carcinoma cell lines. Trichostatin significantly inhibited the proliferation of all six cell lines examined in dose-dependent manner with IC50 of about 125-250 nM. Trichostatin (72-h incubation) induced a G1 phase arrest in ACHN, Caki-1, Caki-2 and Renca cell lines and a G2-M phase arrest in A498 cells. When we examined the effects of this drug on ACHN cells, trichostatin decreased the levels of CDK4, CDK6, cyclin D1 and cyclin A proteins. p27 protein was increased by trichostatin. In addition, trichostatin markedly enhanced the binding of p27 with CDK2 and CDK4. Furthermore, the activities of CDK2, CDK4- and CDK6-associated kinase were reduced and the lack of the CDK activity was paralleled by increased hypophosphorylation of Rb protein. Trichostatin also induced apoptosis in all the renal cell carcinoma cell lines. Apoptotic process of ACHN cells was associated with the changes of Bcl-2, caspase-9, caspase-3, caspase-7 proteins as well as mitochondria transmembrane potential (deltapsim) loss. Taken together, these results demonstrate that trichostatin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis.
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PMID:Trichostatin inhibits the growth of ACHN renal cell carcinoma cells via cell cycle arrest in association with p27, or apoptosis. 1268 81

BAY 43-9006, a multikinase inhibitor that targets Raf, prevents tumor cell proliferation in vitro and inhibits diverse human tumor xenografts in vivo. The mechanism of action of BAY 43-9006 remains incompletely defined. In the present study, the effects of BAY 43-9006 on the antiapoptotic Bcl-2 family member Mcl-1 were examined. Treatment of A549 lung cancer cells with BAY 43-9006 diminished Mcl-1 levels in a time- and dose-dependent manner without affecting other Bcl-2 family members. Similar BAY 43-9006-induced Mcl-1 downregulation was observed in ACHN (renal cell), HT-29 (colon), MDA-MB-231 (breast), KMCH (cholangiocarcinoma), Jurkat (acute T-cell leukemia), K562 (chronic myelogenous leukemia) and MEC-2 (chronic lymphocytic leukemia) cells. Mcl-1 mRNA levels did not change in BAY 43-9006-treated cells. Instead, BAY 43-9006 enhanced proteasome-mediated Mcl-1 degradation. This Mcl-1 downregulation was followed by mitochondrial cytochrome c release and caspase activation as well as enhanced sensitivity to other proapoptotic agents. The caspase inhibitor Boc-D-fmk inhibited BAY 43-9006-induced caspase activation but not cytochrome c release. In contrast, Mcl-1 overexpression inhibited cytochrome c release and other features of BAY 43-9006-induced apoptosis. Conversely, Mcl-1 downregulation by short hairpin RNA enhanced BAY 43-9006-induced apoptosis. Collectively, these findings demonstrate that drug-induced Mcl-1 downregulation contributes to the proapoptotic effects of BAY 43-9006.
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PMID:The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. 1600 48

Anaemia which develops as a consequence of malignancies is often treated using recombinant human erythropoietin (rhEpo). Epo is now known as an anti-apoptotic factor for a wide range of cell types that express Epo receptors (EpoRs) and its co-use with cancer therapies can act detrimentally to diminish therapy-induced apoptosis. This had not been analyzed for renal cell carcinomas (RCCs). We examined the influence of rhEPO on the ability of cisplatin to induce apoptosis in RCCs. Two RCC cell lines (SN12K1 and ACHN) were compared with a non-RCC renal epithelial cell line (HK2). Cells were treated with 50 microM cisplatin with and without 200 IU/mL rhEpo and were compared for apoptosis, mitosis and protein expression of EpoR, nuclear factor-kappaB (NFkappaB), protein kinase C (PKC), Bcl-2, Bax and cyclin-D1. Experiments were repeated with PKC promotion (PMA, 20 nM) or inhibition (H7, 10 microM). rhEpo reduced cisplatin-induced apoptosis in RCCs (p < 0.01), compared with HK-2s. EpoR expression was increased only in SN12K1 with rhEpo, with and without cisplatin. NFkappaB, Bax and Bcl-2 expression was unchanged. PKC protein expression was significantly reduced in cisplatin-treated RCCs with rhEpo, correlating with reduced apoptosis. When the PKC pathway was inhibited in these cells, levels o apoptosis returned to normal for cisplatin treatment, indicating activation of the PKC pathway by rhEpo. PMA promotion increased mitosis only in the RCCs, with and without rhEpo (p < 0.05). In summary, rhEPO reduced cisplatin-induced apoptosis of RCCs and promoted their mitosis via PKC-dependent pathways. This information indicates caution for use of rhEpo in RCC patients for anemias.
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PMID:Erythropoietin reduces cisplatin-induced apoptosis in renal carcinoma cells via a PKC dependent pathway. 1807 99

One of the impeding factors in the effective treatment of metastatic renal cell carcinoma (RCC) is their intrinsic and acquired resistance to chemotherapeutics. Many studies have shown that drug resistance, at least in part, is mediated by the upregulation of anti-apoptotic (Bcl-2) and multidrug resistance molecules (MDR-1 and MRP-1) by the transcription factor nuclear factor kappa B (NF-kappaB). Combining NF-kappaB inhibitors with conventional chemotherapeutics could overcome resistance of cancer cells. In this study, we examined the synergistic effect of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, and cisplatin, on two human metastatic RCC cell lines ACHN and SN12K1. Individual non-toxic concentrations of PDTC and cisplatin, when combined, synergistically induced a significant increase in apoptosis of the two RCC cell lines. In ACHN cells, the groups with nuclear translocation of NF-kappaB showed resistance to apoptosis, but in SN12K1 cells, the groups with NF-kappaB translocation were susceptible to apoptosis. The combination treatment significantly decreased the transcription activity of all NF-kappaB subunits in both cell lines. Anti-apoptotic proteins Bcl-2 and Bcl-(XL) were significantly decreased in the combination therapy group of both cell lines, but MDR-1 was decreased only in the ACHN cells. No changes in MRP-1 were observed in any of the treatment groups. The results demonstrate the potential of PDTC to be an adjunct therapeutic agent. The major mechanism of the synergistic effect appears to be mediated by the inhibition of transcription activity of NF-kappaB rather than its expression, and the resultant decrease in the anti-apoptotic proteins Bcl-2 and Bcl-(XL).
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PMID:Inhibition of nuclear factor kappa B transcription activity drives a synergistic effect of pyrrolidine dithiocarbamate and cisplatin for treatment of renal cell carcinoma. 1985 4

Anisomycin is known to inhibit protein synthesis and induce ribotoxic stress. In this study, we investigated whether anisomycin treatment could modulate TRAIL-mediated apoptosis in human renal carcinoma Caki cells. We found that anisomycin treatment (10-15 nM) alone had no effect on the level of apoptosis, but a combination treatment of anisomycin and TRAIL significantly increased the level of apoptosis in human renal carcinoma (Caki, ACHN and A498), human glioma (U251MG), and human breast carcinoma (MDA-MB-361 and MCF7) cells. Anisomycin treatment led to the down-regulation of Bcl-2 expression at the transcriptional level, and the over-expression of Bcl-2 inhibited the apoptosis induced by the combination treatment of anisomycin and TRAIL. Furthermore, anisomycin treatment resulted in the down-regulation of c-FLIP(L) and Mcl-1 at the post-transcriptional level, and the over-expression of c-FLIP(L) and Mcl-1 blocked the induction of apoptosis caused by the combination treatment of anisomycin with TRAIL. In contrast, anisomycin treatment had no effect on the levels of TRAIL-mediated apoptosis in mouse kidney cells (TMCK-1) or normal human skin fibroblasts (HSF). Cumulatively, our study demonstrates that anisomycin treatment enhances TRAIL-mediated apoptosis through the down-regulation of Bcl-2, c-FLIP(L) and Mcl-1 at the transcriptional or post-transcriptional level.
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PMID:Anisomycin treatment enhances TRAIL-mediated apoptosis in renal carcinoma cells through the down-regulation of Bcl-2, c-FLIP(L) and Mcl-1. 2326 49

The anti-tumor effects of arsenic trioxide (ATO) were well established in acute promyelocytic leukemia, but not in renal cell carcinoma (RCC). Recent evidences indicate that galectin-3 (Gal-3) plays an anti-apoptotic role in chemotherapy induced tumor cell death. This study was intended to clarify the exact roles of Gal-3 performed in ATO-induced apoptosis in RCC cells. Weak apoptosis was observed in Gal-3-positive RCC cells (Caki-1, Caki-2, 786-0, and ACHN) following ATO treatment. However, ATO treatment upregulated Gal-3 expression concurrently caused a Synexin-cooperated translocation of Gal-3 from the nucleus to the cytoplasm. Gal-3-knockdown cells were more sensitive to ATO treatment as indicated by a strong mitochondria-dependent apoptosis following ATO treatment. Meanwhile, Gal-3 was found to inhibit ATO-induced apoptosis through enhancing Bcl-2 expression and stabilizing mitochondria. To confirm the results obtained from genetic method, we employed a Gal-3 inhibitor, modified citrus prectin (MCP), and co-treated the RCC cells with ATO. The cells showed an increased apoptosis in the syngeneic application of Gal-3 inhibition and ATO compared with ATO application alone. Based on these results, we conclude that Gal-3 inhibition sensitizes human renal cell carcinoma cells to ATO treatment through increasing mitochondria-dependent apoptosis. Our studies implicate synergetic application of ATO and Gal-3 inhibition as a potential strategy for RCC treatment.
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PMID:Galectin-3 inhibition sensitizes human renal cell carcinoma cells to arsenic trioxide treatment. 2391 26


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