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)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to exert selectively cytotoxic activity against many tumor cells but not normal cells. In this study, we evaluated the antitumor activity of TRAIL and cisplatin (CDDP) both separately and combined in the human ovarian cancer cell lines. In vitro study showed that TRAIL elicited significant cell apoptosis of cell lines 3AO, SKOV3, and OVCAR3 in a dose- and time-dependent manner (P < 0.05), while normal ovarian epithelial cells were resistant; this toxicity-free effect may be the result of upregulation of TRAIL receptors DcR1 and DcR2. Combined TRAIL and CDDP therapy produced more profound cell killing in 3AO cells than each alone (P < 0.05), and CDDP could upregulate the expression of both death and decoy TRAIL receptors. To further evaluate the apoptosis-inducing effects of TRAIL and the combination therapy, the abdominally and subcutaneously spread tumors in nude mice via inoculation of 3AO cells were established, and treatment of TRAIL resulted in a dose- and time-dependent inhibition of tumor growth while slight damage was observed in normal tissues. Furthermore, combined TRAIL and CDDP therapy had a synergistic effect in the regression of established ovarian cancer xenografts than TRAIL treatment alone (P < 0.05). We also examined the apoptosis-related gene expression in the transplantation tumors after TRAIL treatment, and the data suggested that the intracellular mechanism of TRAIL may be associated with downregulation of Bcl-2 and upregulation of CD95 and Apo2.7.
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PMID:Synergistic antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand combined with cisplatin in ovarian carcinoma cell lines in vitro and in vivo. 1668 23

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL, APO-2L) is a mediator of cell death that preferentially targets cancer cells. The potential of TRAIL as a chemotherapeutic agent is limited, however, because of the emergence of TRAIL resistance. Furthermore, recent studies have demonstrated that alternative TRAIL signaling is unmasked in TRAIL resistant cells. In these cells, the predominant effect of TRAIL receptor activation is the activation of nuclear factor-kappaB (NF-kappaB), which promotes tumor metastases and invasion. TRAIL resistance can occur at the level of the death inducing signaling complex via upregulation of cFLIP or via an increase in antiapoptotic proteins of the Bcl-2 family. A paradigm emerges from this information, that chemotherapy, targeting NF-kappaB, cFLIP, or antiapoptotic proteins of the Bcl-2 family, in combination with TRAIL maybe more rational than TRAIL therapy alone.
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PMID:TRAIL resistance results in cancer progression: a TRAIL to perdition? 1678 86

Tumor targeting is an important issue in cancer gene therapy. We have developed a light-specific transduction method, named photochemical internalization (PCI), to enhance gene expression from adenoviral vectors selectively in illuminated areas. Tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in cancer cells, and the aim of this study was to investigate the potential of PCI to enhance transgene expression from AdhCMV-TRAIL and evaluate its impact on apoptotic induction in the two human colorectal cancer cell lines HCT116 and WiDr. PCI-mediated delivery of AdhCMV-TRAIL enabled an increased expression of TRAIL, induced a synergistic reduction in cell viability compared to the individual action of AdhCMV-TRAIL and photochemical treatment, and enhanced the induction of apoptosis demonstrated by an increase in cytoplasmic histone-associated DNA fragments, caspase-8 and caspase-3 activation, PARP cleavage and a decrease in the mitochondrial membrane potential. The synergistic effect could be related to the enhanced TRAIL expression in PCI-treated samples and a modest sensitization of the cancer cells to TRAIL induced apoptosis due to the photochemical treatment. Furthermore, an increased cleavage of Bid and a cell line dependent reduction in the expression levels of anti-apoptotic Bcl-2 family members were observed and could possibly contribute to the enhanced apoptotic level in samples exposed to the combined treatment. The presented results indicate that photochemically mediated delivery of AdhCMV-TRAIL allows a selective enhancement in cell killing, and suggest that PCI may be relevant and advantageous for therapeutic gene delivery in vivo.
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PMID:Photochemically mediated delivery of AdhCMV-TRAIL augments the TRAIL-induced apoptosis in colorectal cancer cell lines. 1720 62

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent as it selectively kills tumor cells but spares normal cells. Resistance to TRAIL by tumor cells limits its therapeutic use. We have previously shown that protein kinase C-epsilon (PKCepsilon) acts as an antiapoptotic protein in MCF-7 breast cancer cells. In the present study, we have investigated the mechanism(s) by which PKCepsilon contributes to TRAIL resistance. Overexpression of PKCepsilon inhibited caspase-8 and -9 activation, release of mitochondrial cytochrome c and cell death induced by TRAIL, but did not interfere with the recruitment of caspase-8 to the death-inducing signaling complex. Knockdown/inhibition of PKCepsilon resulted in enhanced sensitivity to TRAIL. The level of Bcl-2 was increased and Bid was decreased by PKCepsilon at both the protein and mRNA level but PKCepsilon had no effect on Bax. Knockdown of Bcl-2 by siRNA reversed TRAIL resistance in PKCepsilon-overexpressing cells, whereas depletion of Bid contributed to TRAIL resistance in MCF-7 cells. A decrease in Bid content was also associated with inhibition of TRAIL-induced caspase-8 activation. Furthermore, PKCepsilon depletion or overexpression of DN-PKCepsilon was associated with a decrease in Bcl-2 protein level. Thus, our results suggest that PKCepsilon acts upstream of mitochondria and mediates TRAIL resistance via both Bcl-2 and Bid in MCF-7 cells.
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PMID:Downregulation of Bid is associated with PKCepsilon-mediated TRAIL resistance. 1718 22

Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) selectively induces apoptosis in transformed cells. Normal cells and certain tumor cells can evade Apo2L/TRAIL induced cell death, but the determinants of Apo2L/TRAIL sensitivity are poorly understood. To better understand the factors that contribute to Apo2L/TRAIL resistance, we characterized two colon carcinoma lines with pronounced differences in Apo2L/TRAIL sensitivity. Colo205 cells are highly sensitive to Apo2L/TRAIL whereas Colo320 cells are unresponsive. Components of the DISC (death inducing signaling complex) could be immunoprecipitated from both cell lines in response to Apo2L/TRAIL. Sensitizing agents including a proteasome inhibitor conferred Apo2L/TRAIL sensitivity in Colo320 cells, indicating that the apoptotic machinery was intact and functional. We specifically suppressed the expression of Bcl-2, FLIP or XIAP in Colo320 cells. Downregulation of either FLIP or XIAP but not Bcl-2 restored sensitivity of Colo320 cells to Apo2L/TRAIL. Moreover, stable knockdown of XIAP expression in Colo320 subcutaneous tumors resulted in suppression of tumor growth and sensitivity to Apo2L/TRAIL in vivo. Our results indicate that only a specific subset of anti-apoptotic proteins can confer resistance to Apo2L/TRAIL in Colo320 cells. Elucidation of the factors that contribute to Apo2L/TRAIL resistance in tumor cells may provide insight into combination therapies with Apo2L/TRAIL in a clinical setting.
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PMID:Expression of anti-apoptotic factors modulates Apo2L/TRAIL resistance in colon carcinoma cells. 1744 Aug 16

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells and, in combination with other agents, could enhance tumor therapy. We explored the combined therapeutic effects of a secretable form of (S) TRAIL-induced apoptosis and the downregulation of Bcl-2 in human gliomas. We constructed a lentiviral delivery system: 1) for the expression of short hairpin (sh) RNA to downregulate Bcl-2 and for the expression of S-TRAIL to induce apoptosis in glioma cells; and 2) to follow delivery in vitro and the fate of tumors in real time in vivo. We demonstrate that lentiviral-mediated simultaneous downregulation of Bcl-2 and S-TRAIL-induced apoptosis leads to an increased expression of activated caspase-3 and caspase-7, thus resulting in accelerated S-TRAIL-mediated apoptosis in glioma cells in vitro. Using a highly malignant human glioma model expressing EGFRvIII and firefly luciferase, we show that the combined effect of Bcl-2 downregulation and S-TRAIL-induced apoptosis results in complete eradication of gliomas compared to S-TRAIL monotherapy. These results show that simultaneous triggering of TRAIL-mediated death receptor pathway and downregulation of Bcl-2 by shRNA leads to enhanced eradication of gliomas and serves as a template in developing and monitoring combination therapies for the treatment of drug-resistant cancers.
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PMID:Tumor therapy mediated by lentiviral expression of shBcl-2 and S-TRAIL. 1753 49

Lipoxygenases induce malignant tumor progression and lipoxygenase inhibitors have been considered as promising anti-tumor agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. Combined treatment with nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, and TRAIL markedly induced apoptosis in Jurkat T-cell leukemia cells at suboptimal concentrations for each agent. The combined treatment efficiently activated caspase-3, -8 and -10, and Bid. The underling mechanism by which NDGA enhanced TRAIL-induced apoptosis was examined. NDGA did not change the expression levels of anti-apoptotic factors, Bcl-x(L), Bcl-2, cIAP-1, XIAP and survivin. The expression of death receptor-related genes was investigated and it was found that NDGA specifically up-regulated the expression of death receptor 5 (DR5) at mRNA and protein levels. Down-regulation of DR5 by small interfering RNA prevented the sensitizing effect of NDGA on TRAIL-induced apoptosis. Furthermore, NDGA sensitized prostate cancer and colorectal cancer cells to TRAIL-induced apoptosis. In contrast, NDGA neither enhanced TRAIL-induced apoptosis nor up-regulated DR5 expression in normal peripheral blood mononuclear cells. Another lipoxygenase inhibitor, AA861, also up-regulated DR5 and sensitized Jurkat and DU145 cells to TRAIL. These results indicate that lipoxygenase inhibitors augment the apoptotic efficiency of TRAIL through DR5 up-regulation in malignant tumor cells, and raise the possibility that the combination of lipoxygenase inhibitor and TRAIL is a promising strategy for malignant tumor treatment.
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PMID:Lipoxygenase inhibitors induce death receptor 5/TRAIL-R2 expression and sensitize malignant tumor cells to TRAIL-induced apoptosis. 1764 80

Myelodysplastic syndrome (MDS), previously known as preleukemia, comprises a spectrum of heterogeneous, clonal disorders of hematopoiesis. A patient's life expectancy can range from a few months to more than a decade. Recent studies provide some insight into the pathophysiology of MDS. One mechanism contributing to the constellation of hypercellular marrow and peripheral blood cytopenia is a significant increase in programmed cell death (apoptosis) in hematopoietic cells. Tumor necrosis factor (TNF)-alpha, Fas ligand, TNF-related apoptosis-inducing ligand, and other proapoptotic cytokines are upregulated in early-stage/low-risk MDS, and neutralization of these signals can improve hematopoiesis. TNF-related apoptosis inducing ligand induces apoptosis preferentially in clonal cells, which can contribute to containment of the clone. In a proportion of patients, MDS will eventually evolve to acute leukemia. This progression has been correlated with upregulation of nuclear factor kappaB; altered expression of adaptor molecules, such as Flice inhibitory protein; and enhanced activity of antiapoptotic members of the Bcl-2 and inhibitors of apoptosis protein families. Also, the ratio of TNF receptors 1 and 2 changes in favor of receptor 2. The role of the microenvironment in the pathophysiology and progression of MDS has remained controversial, although there is evidence that stroma and matrix components, and their interactions with clonal cells, play an important role. Microarray gene-expression studies are consistent with dysregulation of apoptosis, but not all data are in agreement.
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PMID:Apoptosis and antiapoptotic mechanisms in the progression of myelodysplastic syndrome. 1797 24

Tumor necrosis factor (TNF) is known to be a mediator of a variety of cellular responses including apoptotic death or proliferation depending on the target cell and the environmental conditions. We show here that TNF triggers both growth and death signals in NIH 3T3 murine fibroblasts. In cells arrested in G(0) by serum deprivation, TNF drives approximately 50% of them to enter the cell cycle, but kills the cells that remain quiescent. The presence of serum prevents toxic effects of TNF, suggesting that TNF can cooperate to drive cells through the cell cycle, but is unable to do so by itself and alternatively it triggers death signals in cells unable to proliferate. Interestingly, TNF induces a similar toxic effect in cells forced to stay at the G(1)/S border, S or M phases. We have explored the TNF apoptotic pathway in arrested cells. This mechanism is not due to the loss of the anti-apoptotic capacity of NFkappaB and is mediated by mitochondria since Bcl-2 overexpression partially inhibits cell death. There are, however, interesting differences in the kinetics of mitochondrial events which indicate that this form of sensitization to TNF leads to an apoptotic mechanism different from that observed after sensitization by RNA synthesis inhibition.
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PMID:TNF triggers mitogenic signals in NIH 3T3 cells but induces apoptosis when the cell cycle is blocked. 1799 51

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors are promising targets for the selective eradication of tumor cells while sparing normal cells. Currently, both recombinant TRAIL proteins and TRAIL receptor agonistic antibodies are being tested in the clinic, showing encouraging antitumor activities and mild side effects. Unfortunately, resistance to TRAIL therapy is frequently encountered requiring combined treatments with sensitizing agents. Standard chemotherapeutics can enhance TRAIL sensitivity; however, more specific and less toxic agents are needed to exploit the full antitumor potential of TRAIL. Here, a brief overview of the TRAIL signaling pathway is given together with a short description of early results obtained with TRAIL therapy in the clinic. Mechanisms of TRAIL resistance and ways to overcome these by targeted agents that either neutralize apoptotic blockades or suppress prosurvival signals also triggered by TRAIL are highlighted, such as inhibitors of IAPs, Bcl-2 family members, HDACi, and modulators of NF-kappaB, Raf and EGFR signaling.
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PMID:TRAIL and cancer therapy. 1832 93


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