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)

The hepatic cancer HA22T/VGH cell line, which constitutively expresses activated nuclear factor-kappaB (NF-kB), was chosen as a model to examine the antitumor activity of curcumin, also in relationship to its possible influences on the activation of the transcription factor and on the expression of the inhibitory of apoptosis proteins (IAPs) and of other NF-kB target genes. Curcumin exerted cell growth inhibitory and apoptotic effects, related, at least part, to free radical generation and mainly dependent on caspase-9 and -3 activation. The combination of curcumin with cisplatin resulted in a synergistic antitumor activity and that with doxorubicin in additivity or sub-additivity. Curcumin exerted biphasic changes in the levels of NF-kB, with an increase at 8 h after its administration and a decrease at 16 h. For the combinations of curcumin with the other drugs, the levels of the transcription factor were lower than those predicted from the effects of the single agents, especially with a blunting of the remarkable increases in NF-kB activation induced by doxorubicin. Except for Bcl-2, the HA22T/VGH cells expressed different other genes, including the IAPs, implicated in cell proliferation and survival. Curcumin determined early changes in COX-2 and c-myc mRNAs, which were down-regulated, and in livin mRNA, which was up-regulated. Later it decreased Bcl-X(L) mRNA and increased Bcl-X(S) and c-IAP-2 mRNAs. Cisplatin and doxorubicin exerted distinct effects on gene expression. The cytotoxic interactions between curcumin and these agents were accompanied by synergistic (in particular with cisplatin) or additive effects of decrease in the expression of different genes, including c-myc, Bcl-X(L), c-IAP-2, NAIP and XIAP. However, the combinations attenuated also certain other influences on mRNA expression of the single agents, like, for example, the increases in Bcl-X(s) given by curcumin and doxorubicin. Overall, the effects of the drugs, alone or in combination, on tumor cell growth, cell death and gene expression did not show a simple relationship to the relative influences on NF-kB activation, inferring that they can be due also to other mechanisms.
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PMID:Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in NF-kB activation levels and in IAP gene expression. 1591 Nov 1

We have earlier reported that the inhibition of apoptosis in head and neck squamous cell carcinomas (HNSCC) is because of upregulated expression of Bcl-2, Bcl-X(L) and Survivin. Hence, we addressed the question whether antisense approach towards these inhibitors of apoptosis could restore the apoptosis in HNSCC. Further, we wanted to see whether chemotherapeutic efficacy of Cisplatin and Etoposide could be enhanced by using these drugs in combination with antisense oligonucleotides in human laryngeal carcinoma HeP2 and tongue carcinoma Cal27 cells. The effect of these antisense oligonucleotides was examined on the mRNA expression by RT-PCR and on protein expression by Western blotting. Apoptosis was measured by flowcytometry, TUNEL assay and caspase-3 activity assay. Treatment of HeP2 and Cal27 cells with 400 nM antisense oligonucleotides against Bcl-2, Bcl-X(L) and Survivin for 48 hrs decreased their expression both at the mRNA as well as at the protein level, resulting in the induction of apoptosis. Treatment of HeP2 and Cal27 cells with these antisense oligonucleotides augmented Cisplatin and Etoposide induced apoptosis. Our findings emphasize the importance of Bcl-2, Bcl-X(L) and Survivin as survival factors in HNSCC cells. Antisense treatment against these survival factors in combination with lower doses of chemotherapy offers potential as a less toxic chemoadjuvant therapy.
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PMID:Antisense-mediated downregulation of anti-apoptotic proteins induces apoptosis and sensitizes head and neck squamous cell carcinoma cells to chemotherapy. 1591 59

The aim of this study was to develop novel and less toxic therapy for human head and neck squamous cell carcinoma (HNSCCs) and to investigate the mechanism of quercetin-induced apoptosis in human laryngeal HeP2 cells and its effect on cisplatin induced apoptosis. Priming the cells with quercetin (40 microM) increased the apoptosis induced by cisplatin alone from 18.7% to 42.2% in HeP2 cells. Quercetin induced apoptosis via inhibition of Akt/PKB phosphorylation, an upstream kinase of pro-survival protein kinase cascade. Inhibition of Akt phosphorylation was coupled with a significant decrease of anti-apoptotic Bcl-2 and Bcl-XL. Quercetin caused a downregulation of Cu-Zn Superoxide Dismutase which perhaps led to an increase of reactive oxidative stress (ROS). The decrease of Bcl-2 and Bcl-XL along with this oxidative stress caused release of mitochondrial cytochrome c into the cytosol and subsequent induction of pro-caspase-9 processing. Inhibition of heat shock proteins may be another mechanism for the pro-apoptotic activity of quercetin. Cisplatin induced apoptosis appears to be partly due to induction of JNK activity which leads to the activation of endonucleases. Increased JNK activity led to increased phosphorylation of c-Fos. Cisplatin additionally appears to induce apoptosis by down-regulating the enzyme Nitric Oxide Synthase (NOS). Cisplatin also acts by increasing pro-apoptotic Bax concentration in the cells thereby leading to caspase-9 activation via the mitochondrial pathway. These results support the fact that quercetin and cisplatin act by separate pathways and demonstrate interactions between the pathways that result in synergistic actions. Possibly of greater potential value is the interaction of a conventional cytotoxic drug (cisplatin) and a nontoxic chemopreventive agent (quercetin) thereby allowing the use of less toxic doses of chemotherapy for treatment of HNSCCs.
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PMID:Molecular pathways in the chemosensitization of cisplatin by quercetin in human head and neck cancer. 1608 93

Malignant mesothelioma (MM) is an aggressive and highly chemo-resistant tumour. In this study, we examined cisplatin-induced apoptosis in mouse models of this disease and investigated the role of constitutive and inducible expression of apoptosis related genes in this process. All of the four mouse MM cell lines examined expressed Bax, Bcl-xL, c-Myc, and caspase-3 but not Bcl-2. Cisplatin-induced apoptosis characterised by DNA fragmentation and cell death while caspase-3/7 was activated in 3 of 4 cell lines. Quantitation of basal gene expression showed significant differences but there was no correlation between single genes and cisplatin sensitivity. In the AC29 and AB1 models, both cisplatin and TNF-alpha downregulated Bcl-xL gene expression, indicating that this gene was a common transcriptional target in these cells. The findings of the present study provide insights into apoptotic mechanisms in mesothelioma cells and show similar patterns of gene expression to that reported in the human disease.
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PMID:Cisplatin and TNF-alpha downregulate transcription of Bcl-xL in murine malignant mesothelioma cells. 1622 50

Chemotherapy has been used for treatment of breast cancer but with limited success. We characterized the effects of bcl-2 antisense and cisplatin combination therapy in two human isogenic breast carcinoma cells p53(+)MCF-7 and p53(-)MCF-7/E6. The transferrin-facilitated lipofection strategy we have developed yielded same transfection efficiency in both cells. Bcl-2 antisense delivered with this strategy significantly induced more cell death, apoptosis, and cytochrome c release in MCF-7/E6 than in MCF-7, but did not affect Fas level in both cells and activated caspase-8 equally. Cisplatin exerted same effects on cell viability and apoptosis in both cells, but released smaller amounts of cytochrome c while activated more caspase-8 in MCF-7/E6. The combination treatment yielded greater effects on cell viability, apoptosis, cytochrome c release, and caspase-8 activation than individual treatments in both cells although p53(-) cells were more sensitive. The potentiated activation of caspase-8 in the combination treatment suggested that caspase-8-mediated (but cytochrome c-independent) apoptotic pathway is the major contributor of the enhanced cell killing. Thus, bcl-2 antisense delivered with transferrin-facilitated lipofection can achieve the efficacy of killing breast cancer cells and sensitizing them to chemotherapy. Bcl-2 antisense and cisplatin combination treatment is a potentially useful therapeutic strategy for breast cancer irrespective of p53 status.
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PMID:BCL-2 antisense and cisplatin combination treatment of MCF-7 breast cancer cells with or without functional p53. 1622 92

The molecular mechanism underlying chemotherapy-induced apoptosis is often debated because of contradicting reports of its signaling pathway. The focus of this ongoing debate is on the requirement of a death receptor and its role in subsequent activation of caspase-8. Understanding the precise mechanism responsible for apoptosis and identifying molecules targeted by chemotherapy will allow us to develop better therapeutic strategies that target the inherent abnormalities of cancer cells. To show conventional chemotherapy drugs can trigger the caspase cascade, including caspase-8, -9, -3 and DNA fragmentation factor, Jurkat T leukemia cells were treated with cisplatin or etoposide in a dose-dependent and a time-dependent manner. Cisplatin and etoposide all induced apoptosis in wild-type Jurkat T leukemia cells. On the other hand, when a pan-caspase inhibitor zVAD-FMK was pretreated, apoptosis did not occur, indicating that these chemotherapy drugs mediated caspase-dependent apoptosis. However, the chemotherapy drug induction of apoptosis was not inhibited by treatment of zIETD-FMK, a caspase-8 inhibitor. There was no difference in cell death between wild-type and caspase-8 or FADD-deficient Jurkat cells after treatment of chemotherapy drug. In addition, cisplatin-induced apoptosis is abrogated by the overexpression of either Bcl-2 or Bcl-x(L), which diminished changes of mitochondrial membrane potential and decreased the amount of cytochrome c released from mitochondria. Again, cisplatin-induced apoptosis was not diminished by c-FLIP-overexpression, whereas the c-FLIP-overexpressing cells were less sensitive to TRAIL-induced apoptosis than the wild type cells. Therefore, these results indicate that conventional chemotherapy drug-triggered apoptosis is indispensable, and its pathway is independent of the death receptor.
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PMID:Role of death receptor and mitochondrial pathways in conventional chemotherapy drug induction of apoptosis. 1644 62

Cisplatin (CDDP) is a DNA damaging agent and is widely used for treating cancer. While the role of p53 in CDDP-induced cell death has been stressed, evidence exists that CDDP can also kill p53-mutated cells. To investigate the latter mechanism, we performed a comparative study using three different human cell types, SNU-16 (a stomach cancer cell-line), U937 (a leukemic cell-line) and 293T (a kidney fibroblast cell-line), which are defective in terms of p53 activation. A focus was placed on Bcl-2 family proteins, reactive oxygen species (ROS), and mitogen-activated protein kinases. Our results suggest that the ability of CDDP to kill these cells can be mediated by JNK, p38 MAPK and ROS, but not by ERK. It was also found that CDDP can increase the ratio of pro-apoptotic/pro-survival Bcl-2 members. While the importance of these components was found to depend on cell type, JNK was commonly involved in the deaths of all cell types examined. Therefore, the JNK pathway appears to be an ideal target for the modulation of the lethal action of CDDP in multiple types of p53-mutated cells.
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PMID:Cellular components involved in the cell death induced by cisplatin in the absence of p53 activation. 1659 82

Cisplatin is a potent cytotoxic agent commonly used for the treatment of solid tumors. However, tumor cell-acquired resistance to cisplatin-induced apoptosis is a major limitation for efficient therapy, as frequently observed in human lung cancer. Nitric oxide (NO) is a key regulator of apoptosis, but its role in cisplatin-induced cell death and the underlying mechanism are largely unknown. Previous studies indicate increased NO synthase activity and elevated NO production in lung carcinomas, which correlate with the incidence of chemotherapeutic resistance. Here, we show that NO impairs the apoptotic function of cells and increases their resistance to cisplatin-induced cell death in human lung carcinoma H-460 cells. The NO donors sodium nitroprusside and dipropylenetriamine NONOate were able to inhibit cisplatin-induced cell death, whereas the NO inhibitors aminoguanidine and 2-(4-carboxyphenyl)-4,4,5,5-tetra-methylimidazoline-1-oxyl-3-oxide had opposite effect. Cisplatin resistance in H-460 cells is mediated by Bcl-2, and NO up-regulates its expression by preventing the degradation of Bcl-2 via ubiquitin-proteasome pathway. Cisplatin-induced generation of reactive oxygen species causes dephosphorylation and degradation of Bcl-2. In contrast, generation of NO has no effect on Bcl-2 phosphorylation but induces S-nitrosylation of the protein, which inhibits its ubiquitination and subsequent proteasomal degradation. These findings indicate a novel pathway for NO regulation of Bcl-2, which provides a key mechanism for cisplatin resistance and its potential modulation for improved cancer chemotherapy.
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PMID:Nitric oxide regulates cell sensitivity to cisplatin-induced apoptosis through S-nitrosylation and inhibition of Bcl-2 ubiquitination. 1677 13

During apoptosis, engagement of the mitochondrial pathway involves the permeabilization of the outer mitochondrial membrane (OMM), which leads to the release of cytochrome c and other apoptogenic proteins such as Smac/DIABLO, AIF, EndoG, Omi/HtraA2 and DDP/TIMM8a. OMM permeabilization depends on activation, translocation and oligomerization of multidomain Bcl-2 family proteins such as Bax or Bak. Factors involved in Bax conformational change and the function(s) of the distinct domains controlling the addressing and the insertion of Bax into mitochondria are described in this review. We also discuss our current knowledge on Bax oligomerization and on the molecular mechanisms underlying the different models accounting for OMM permeabilization during apoptosis.
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PMID:Mitochondria as the target of the pro-apoptotic protein Bax. 1683 74

Cisplatin is one of the most common DNA-damaging agents used for treating patients with solid tumors such as squamous cell carcinoma (SCC). Unfortunately, significant levels of resistance in SCC cells emerge rapidly following cisplatin treatment. Here we report that the proteasome inhibitor PS-341, the representative of a new class of chemotherapeutic drugs, was capable of inducing apoptosis in cisplatin-resistant SCC cells via the endoplasmic reticulum stress. PS-341 stimulated the phosphorylation of PERK and the unfolded protein response, resulting in the induction of the transcription factor ATF-4. Importantly, the Bcl-2 homology domain 3-only (BH3-only) protein Noxa was found to be strongly induced in cisplatin-resistant SCC cells by PS-341 but not by cisplatin. The knock-down of Noxa using small interference RNA significantly abolished PS-341-mediated apoptosis in SCC cells. Using eIF2alpha mutant mouse embryonic fibroblasts, we found that functional eIF2alpha played an essential role in PS-341-induced Noxa expression. Taken together, our novel findings reveal a direct link between PS-341-induced endoplasmic reticulum stress and the mitochondria-dependent apoptotic pathway and suggest that PS-341 may be utilized for overcoming cisplatin-resistance in human SCC.
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PMID:Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa. 1692 86


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