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)

Combination chemotherapy using paclitaxel with a platinum-based regimen is currently the standard first-line therapy for ovarian cancer after surgical cytoreduction. Whereas cisplatin-paclitaxel combination chemotherapy has shown significant efficacy over previous drug combinations in ovarian cancer, 20-30% of patients fail to respond to this combination. These patients are deemed cisplatin-paclitaxel resistant, although it is unclear whether the tumors are resistant to one or both drugs. Because the options available to ovarian cancer patients for second-line therapy are limited, and knowing that mechanistic differences exist between cisplatin and paclitaxel, we assessed the efficacy of combination drug therapy on cisplatin-resistant (cisplatinR) ovarian cancer cells. We found that paclitaxel induced apoptosis in cisplatinR cells as well as in the cisplatin-sensitive parental cell lines. In cisplatinR C-13 cells, the concomitant addition of cisplatin blocked paclitaxel-induced apoptosis as determined by DNA fragmentation assays, fluorescence microscopy, and flow cytometry. Paclitaxel-induced multimininucleation was also inhibited when the cells were exposed sequentially to paclitaxel and then cisplatin. Cisplatin did not block paclitaxel-induced stabilization of microtubules or prevent paclitaxel-induced loss of Bcl-2 expression in cisplatinR cells. Conversely, paclitaxel did not inhibit p53 protein accumulation by cisplatin. These results suggest that cisplatin blocks paclitaxel-induced apoptosis at a point downstream of Bcl-2 degradation and independent of microtubule stabilization. Our research shows that cisplatin can inhibit the effectiveness of paclitaxel in cispatinR cell lines. Therefore, the establishment of a clinical protocol to evaluate the efficacy of paclitaxel alone versus another second-line regimen in patients with cisplatin-paclitaxel-resistant ovarian cancer is warranted.
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PMID:Cisplatin inhibits paclitaxel-induced apoptosis in cisplatin-resistant ovarian cancer cell lines: possible explanation for failure of combination therapy. 1034 53

We have assessed in detail the effect of cisplatin-activated programmed cell death in the cisplatin-sensitive human ovarian cancer cell line A2780 and two drug-resistant subclones, CP70 and C30. To determine whether the differential extent of apoptosis observed between the sensitive and resistant ovarian cancer cell lines was the result of dissimilar upstream signaling events, we assessed the execution of apoptotic events that precede target protein proteolysis and subsequent chromosomal DNA degradation. Proteolytic degradation of procaspase-3 was observed in both the CP70 and C30 cells following IC50 cisplatin treatment, whereas no proteolyzed caspase-3 subunits were detected in the A2780 cells. However, using a direct enzymatic assay measuring cleavage of the synthetic peptide substrate (N-acetyl-Asp-Glu-Val-Asp-p-nitroanilide), activity was detected in extracts prepared from A2780 cells treated at the IC90 level of cisplatin and was 2-3-fold less than that of extracts prepared from CP70 and C30 cells. Because the activation of procaspase-3 by caspase-9 requires the release of cytochrome c into the cytoplasm, we determined the level of cytoplasmic cytochrome c in each cell line in response to cisplatin treatment. Consistent with the caspase-3 activation data, a very small increase in cytoplasmic cytochrome c was observed in A2780 cells following cisplatin treatment, whereas dramatic increases were evident in both the CP70 and C30 cell lines. The expression of the mitochondrial factors Bcl-2, Bcl-x, and Bax was determined because each has been implicated in the regulation or release of cytochrome c at the level of the mitochondria. Bcl-2 and Bcl-xL proteins remained relatively unchanged in expression for over 48 h after exposure to cisplatin in the A2780 cell lines. However, within the same time period, expression of Bcl-2 decreased in the CP70- and C30-resistant cell lines, whereas an increase in Bcl-xL expression was observed. Expression of the proapoptotic Bcl-xS protein was observed in only the resistant CP70 and C30 cell lines independent of cisplatin treatment. A change in the expression of Mr 24,000 Bax to a Mr 21,000 isoform was evidenced in the A2780 cells within 48 h of cisplatin treatment and, to a greater extent, in the CP70 and C30 cells, which also expressed a Mr 16,000 Bax variant. Evidence for an alternative apoptotic pathway in A2780 cells was obtained by demonstrating increased FADD expression in response to cisplatin treatment. These results support a model in which cisplatin-induced programmed cell death in the cisplatin-sensitive A2780 and -resistant CP70 and C30 cells proceeds via caspase-3-independent and -dependent pathways, respectively.
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PMID:Cisplatin-induced apoptosis proceeds by caspase-3-dependent and -independent pathways in cisplatin-resistant and -sensitive human ovarian cancer cell lines. 1039 48

Ovarian cell death is an essential process for the homeostasis of ovarian function in human and other mammalian species. It ensures the selection of the dominant follicle and the demise of excess follicles. In turn, this process minimizes the possibility of multiple embryo development during pregnancy and assures the development of few but healthy embryos. Degeneration of the old corpora lutea in each estrous/menstrual cycle by programmed cell death is essential to maintain the normal cyclicity of ovarian steroidogenesis. Although there are multiple pathways that can determine cell death or survival, crosstalk among endocrine, paracrine and autocrine factors, as well as among protooncogenes, tumor suppressor genes, survival genes and death genes, plays an important role in determining the fate of ovarian somatic and germ cells. The establishment of immortalized rat and human steroidogenic granulosa cell lines and the investigation of pure populations of primary granulosa cells allows systematic studies of the mechanisms that control steroidogenesis and apoptosis of granulosa cells. These cells are the most abundant type of somatic follicular cell. Moreover, crosstalk between p53 and extracellular matrix components such as laminin, fibronectin and basic fibroblast growth factor, between cAMP- and p53-generated signals and between steroid hormones and Bcl-2, can explain some of the fine tuning that controls ovarian steroidogenesis and apoptosis. Further study of the mechanisms of ovarian cell death will lead to a better understanding of the processes involved and permit the formulation of novel strategies for the treatment of ovarian malfunctions, such as polycystic ovarian syndrome and ovarian cancer.
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PMID:Crosstalk Among Multiple Signaling Pathways Controlling Ovarian Cell Death. 1046 Nov 71

Antisense oligonucleotides can block the expression of specific target genes involved in the development of human diseases. Therapeutic applications of antisense techniques are currently under investigation in many different fields. The use of antisense molecules to modify gene expression is variable in its efficacy and reliability, raising objections about their use as therapeutic agents. However, preliminary results of several clinical studies demonstrated the safety and to some extent the efficacy of antisense oligodeoxynucleotides (ODNs) in patients with malignant diseases. Clinical response was observed in some patients suffering from ovarian cancer who were treated with antisense targeted against the gene encoding for the protein kinase C-alpha. Some hematological diseases treated with antisense oligos targeted against the bcr/abl and the bcl2 mRNAs have shown promising clinical response. Antisense therapy has been useful in the treatment of cardiovascular disorders such as restenosis after angioplasty, vascular bypass graft occlusion, and transplant coronary vasculopathy. Antisense oligonucleotides also have shown promise as antiviral agents. Several investigators are performing trials with oligonucleotides targeted against the human immunodeficiency virus-1 (HIV-1) and hepatitis viruses. Phosphorothioate ODNs now have reached phase I and II in clinical trials for the treatment of cancer and viral infections, so far demonstrating an acceptable safety and pharmacokinetic profile for continuing their development. The new drug Vitravene, based on a phosphorothioate oligonucleotide designed to inhibit the human cytomegalovirus (CMV), promises that some substantial successes can be reached with the antisense technique.
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PMID:Antisense oligonucleotides as therapeutic agents. 1049 4

Papillary serous endometrial carcinoma is an aggressive tumor characterized by late-stage presentation, i.p. spread, and poor prognosis. It is histologically similar to serous papillary carcinoma of the ovary. Preclinical studies have shown that adenovirus-mediated expression of p53 in ovarian cancer cell lines causes growth inhibition and apoptosis in vitro and in vivo. Such studies provide the rationale for Phase I Adp53 gene therapy clinical trials in ovarian cancer. In the present study, we compared the efficacy of adenoviral vectors containing p53 (Adp53) or p21 (Adp21) in a papillary serous endometrial tumor cell line (SPEC-2) that contains mutated p53. Growth assays revealed that both Adp53 and Adp21 were efficacious in decreasing cell proliferation as assessed by anchorage-dependent and anchorage-independent growth assays. However, as compared with Adp53, the effects of Adp21 tended to be more transient and less marked. Strikingly, Adp21, but not Adp53, induced a G1 arrest in SPEC-2 endometrial adenocarcinoma cells. In contrast, as assessed by induction of hypodiploid peaks, free DNA ends detected by a terminal deoxynucleotidyl transferase-based assay, and annexin V positivity, p53 was more effective than p21 in inducing cell death by apoptosis. Compatible with the more efficient induction of apoptosis, Adp53, but not Adp21, induced a marked increase in expression of the preapoptotic molecule BAX without a concomitant change in expression of the antiapoptotic mediator Bcl-2. The differential effects of Adp53 and Adp21 on cell cycle progression and apoptosis may be related to the reversibility of p21-induced cell cycle arrest and the irreversibility of p53-induced apoptosis. Thus, at least in the papillary serous endometrial carcinoma cell line SPEC-2, Adp53 may be more effective than Adp21 as a gene therapeutic. Nevertheless, these preclinical studies suggest that papillary serous endometrial carcinoma is a potential target for p53- or p21-mediated gene therapy.
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PMID:Adenovirus-mediated expression of p53 or p21 in a papillary serous endometrial carcinoma cell line (SPEC-2) results in both growth inhibition and apoptotic cell death: potential application of gene therapy to endometrial cancer. 1065 59

Several endogenous or viral inhibitors of apoptosis, including Bcl-2, Bcl-xL, FLIP, p35, and CrmA, have been shown to be cleaved by caspases during apoptosis. In this study, we demonstrate that the endogenous inhibitor of apoptosis, hILP/XIAP, is also cleaved in apoptotic T lymphocytes, generating at least one prominent fragment of 29 kDa. This p29 cleaved fragment was detected in Jurkat cells induced to apoptose by anti-Fas antibody, staurosporin, or VP-16. The cleavage of hILP appears to be caspase mediated because the production of the p29 protein was inhibited by the pan-caspase peptide inhibitor, Z-VAD.FMK. In Jurkat cells engineered to overexpress CrmA, cleavage of hILP in response to anti-Fas antibody or staurosporin was inhibited, whereas overexpression of Bcl-2 abrogated the cleavage in response to VP-16. Cleavage of hILP was also observed in cell-free reactions using in vitro translated hILP and recombinant caspase-3 or -7. Moreover, we found that the p29 hILP fragment retained the ability to bind caspase-3 and -7, as shown previously for full-length or BIR-2 hILP. The p29 cleavage product was also detected during T-cell receptor-mediated apoptosis in peripheral blood lymphocytes from normal donors. Furthermore, tumor-associated T lymphocytes purified from ascites of patients with ovarian cancer expressed fragmented hILP, which was not detected in control T cells purified from peripheral blood of normal donors. Our results suggest that the cleavage of hILP represents an important event in apoptosis of T lymphocytes in both normal and pathological in vivo settings.
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PMID:Inhibitor of apoptosis protein hILP undergoes caspase-mediated cleavage during T lymphocyte apoptosis. 1076 65

Cisplatin is in common use in ovarian cancer therapy, although it is also implicated in cytotoxicity in normal tissue. We have examined the effect of cisplatin alone and in combination with theophylline, a phoshodiesterase inhibitor, on modulation of Bcl-2/Bax expression and induction of apoptosis in human granulosa cells transformed by stable transfection with mutant p53 plus Ha-ras. Theophylline elicited cell death only at relatively high concentrations with an EC50 of 200 microg/ml. Cisplatin exerted its lethal effect with an EC50 of 7 microM. In the presence of 15 or 50 microg/ml of theophylline (in the range used against asthma in humans), the EC50 for cisplatin was reduced to 2 microM or 1.2 microM, respectively. Using fluorescence-activated cell sorting analysis of DNA stained cells and the terminal deoxy-nucleotide tranferase-mediated dUTP nick end-labeling method, we found that even at concentrations of 0. 3 and 1 microM cisplatin, theophylline at 15 and 50 microg/ml increased the incidence of apoptosis in these cells by 3-5-fold, while theophylline alone induced extremely low apoptosis. Neither drug had any measurable effect on Bax protein expression. In contrast Bcl-2 protein expression levels were markedly reduced by theophylline and cisplatin in a dose-dependent manner. The combination of theophylline and cisplatin resulted in a further dramatic reduction in Bcl-2, under-scoring the pronounced synergy of these two drugs. These observations suggest that suppression of Bcl-2 expression may play an important role in mediating the synergistic effect of cisplatin and theophylline on induction of apoptosis in ovarian cancer cells.
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PMID:Theophylline and cisplatin synergize in down regulation of BCL-2 induction of apoptosis in human granulosa cells transformed by a mutated p53 (p53 val135) and Ha-ras oncogene. 1089 29

We conducted a retrospective immunohistochemical evaluation of the prognostic significance of the expression of p53 and the related proteins Bax, Bcl-2, growth arrest and DNA damage (Gadd45), murine double minute 2 (Mdm2) and p21(WAF1/CIP1) in chemonaive tumours taken from 66 patients with ovarian cancer. Ki-67 expression (a marker of cell proliferation) was also evaluated immunohistochemically, while apoptosis within malignant cells was determined with the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL) assay. The expression of each of the following proteins was significantly associated in the tumours (P < 0.05 unless otherwise stated): Bax with Bcl-2 (P < 0.01); Bax with Mdm2; p21(WAF1/CIP1) with Gadd45 (P < 0.01); p21(WAF1/CIP1) with p53; p53 with Mdm2. Univariate analysis showed that expression of p53, Bax, bulk residual disease and International Federation of Gynecology and Obstetricians (FIGO) stage were all strongly correlated with response to chemotherapy (P < 0.01). Similarly, the FIGO stage and Ki-67 expression (P < 0.01), as well as pathological subtype and bulk residual disease (P < 0.05), were prognostic factors for disease progression. The FIGO stage and Ki-67 expression were significant prognostic factors for overall survival (P < 0.01), with Gadd45 expression and pathological subtype also significant (P < 0.05) in a univariate analysis. Multivariate analysis for response to chemotherapy showed that expression of p53, Bax and FIGO stage were all independent prognostic factors (P < 0.01). The FIGO stage was the most important independent prognostic factor for progression and survival on multivariate analysis (P < 0.01). However, Ki-67 expression was also an independent prognostic factor for disease progression (P < 0.05) and approached significance for survival (P = 0.055). Taken together, these data suggest that determination of Ki-67 expression could supplement established prognostic factors.
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PMID:p53 and related proteins in epithelial ovarian cancer. 1109 5

Ovarian cancer is among the most lethal cancers in women because of its high metastatic potential and lack of response to therapy. An experimental model to study this disease was developed using a transformed granulosa cell line expressing a mutant p53 and Ha-ras. When injected into the ovary of nude mice in the presence of laminin-1, tumors develop in the ovary and peritoneum and metastasize to various organs, leading to death within 21 days. In contrast, when cells were injected in the presence of gelatin, development of tumors was slower and no metastases were observed by day 21. Here we investigated the possible mechanism by which laminin-1 exerts its promotion of tumorigenesis and metastasis. Cells were co-injected with laminin-1 and active laminin peptides from the alpha1; (A13: RQVFQVAYIIIKA, A12: WVTVTLDL RQVFQ, AG73: LQVQLSIR, IKVAV) and beta1 (YIGSR) chains. Ovarian tumor growth and metastasis were increased in the presence of laminin-1 plus either AG73 peptide, IKVAV, or A13, and were significantly reduced in the presence of A12 or YIGSR. Expression of Bcl-2 and Mdm2 was higher by 3.5- and about 100-fold, respectively, in ovarian tumors grown in the presence of laminin compared to tumors grown in the presence of gelatin. Moreover, peptides A13 and AG73 further elevated Bcl-2 expression by 6- and 7-fold respectively, while IKVAV yielded expression similar to laminin-1. YIGSR and A12 reduced the expression of Bcl-2 by 7- and 3-fold, respectively, compared to treatment with laminin-1. A13 and AG73 increased Mdm2 expression by 1.8- and 1.3-fold, respectively, while IKVAV, A12, and YIGSR were without effect. Thus, laminin-1 exerts its proliferative effect on the development of ovarian tumors via upregulation of survival genes such as Bcl-2 and Mdm2. Peptides A13 and AG73 (which increased tumor growth and spread) enhance the expression of these genes and A12 and YIGSR (which decrease tumor growth and spread) attenuate their expression. IKVAV probably enhances tumor growth and metastasis by another mechanism.
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PMID:Role of laminin in ovarian cancer tumor growth and metastasis via regulation of Mdm2 and Bcl-2 expression. 1129 35

Most ovarian neoplasms arise from the ovarian surface epithelium (OSE), and multiple growth factors have been implicated to influence the transformation from OSE. The present study was performed to investigate the role of activin and transforming growth factor-beta (TGFbeta) in normal and neoplastic OSE cells. An immortalized OSE cell line (IOSE-29) was generated from normal OSE by transfecting simian virus 40 large T antigen and was rendered tumorigenic after subsequent transfection with the E-cadherin gene (IOSE-29EC). The activin/inhibin subunits and activin receptors were expressed at both messenger ribonucleic acids and protein levels in these cells, suggesting that activin may have an autocrine role in neoplastic OSE cells. Treatments with activin (1-100 ng/mL) resulted in a significant decrease in cell proliferation in both IOSE-29 and IOSE-29EC cells, although we have shown that it stimulated the growth of ovarian cancer cells and had no effect on normal OSE. This inhibitory effect was attenuated with cotreatment with follistatin. Treatment with TGFbeta (0.1-10 ng/mL) also significantly decreased the proliferation of normal, IOSE-29, and IOSE-29EC cells in a dose-dependent manner. In addition, treatments with both activin and TGFbeta resulted in an increase in DNA fragmentation in IOSE-29EC cells in a dose-dependent manner. This apoptotic effect of activin was attenuated by cotreatment with follistatin. Treatment with TGFbeta (1 and 10 ng/mL) resulted in a significant decrease in Bcl-2 protein (up to 50%) in IOSE-29EC, whereas no difference was observed in Bax protein levels. Therefore, down-regulated Bcl-2 by TGFbeta may eventually induce apoptosis in IOSE-29EC cells. In contrast, no difference was observed in Bax and Bcl-2 protein expression after treatment with activin. In conclusion, the present study indicates that activin and TGFbeta inhibited growth and induced apoptosis in early neoplastic (IOSE-29) and tumorigenic OSE (IOSE-29EC) cells. Furthermore, antiapoptotic Bcl-2 protein was down-regulated by TGFbeta, whereas no difference was produced in Bax protein by activin or TGFbeta treatment or in Bcl-2 protein by activin. These results suggest that activin and TGFbeta may play a role in growth inhibition and induction of apoptosis in early neoplastic and tumorigenic stage of ovarian cancer.
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PMID:The regulation of apoptosis by activin and transforming growth factor-beta in early neoplastic and tumorigenic ovarian surface epithelium. 1134 17


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