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)

Synovial cell hyperplasia is a characteristic of patients with RA. Excessive proliferation of RA synovial cells is, in part, responsible for the synovial cell hyperplasia. In addition, synovial cell death that would reduce synovial cell number may be defective, leading to the hyperplasia. Thus, the defective control of cell death as well as cell proliferation may be of central importance in the pathogenesis of RA. In this study we analysed effects of proinflammatory cytokines on Fas/Fas ligand (FasL)-induced synovial cell apoptosis, and evaluated apoptosis-associated protein expression in the synovial cells in patients with RA. RA synovial cells expressed Fas antigen and lymphocytes infiltrating into RA synovium expressed FasL. Apoptotic synovial cells were detected within the sublining layer of RA synovium. Anti-Fas MoAb induced apoptosis of RA synovial cells in vitro, and proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and IL-1beta, but not IL-6 or IL-8, inhibited the anti-Fas-induced apoptosis accompanying up-regulation of Bcl-2 protein expression and reduced expression of CPP32 and ICH-1L. Immunohistochemical study revealed that CPP32 and ICH-1L were expressed weakly in the RA synovial lining cells compared with osteoarthritis (OA) synovial lining cells. Thus, we found that although RA synovial cells could die via apoptosis through Fas/FasL pathway, apoptosis of synovial cells was inhibited by proinflammatory cytokines present within the synovium. Inhibition of apoptosis by the proinflammatory cytokines may contribute outgrowth of synovial cells that leads to pannus formation and the destruction of joints in patients with RA.
Clin Exp Immunol 1998 Oct
PMID:Modulation by proinflammatory cytokines of Fas/Fas ligand-mediated apoptotic cell death of synovial cells in patients with rheumatoid arthritis (RA). 976 13

There is a dogma in tumor immunology that tumor-infiltrating lymphocytes (TIL) are defective based on their lack of antitumoral efficacy in vivo and on impaired response to in vitro functional tests. However, TIL have been compared usually with peripheral blood T lymphocytes, raising doubts on the conclusions drawn. Therefore, we compared TIL from B cell non-Hodgkin's lymphomas (NHL) with T cells from nonmalignant secondary lymphoid organs. NHL-TIL were unresponsive to activation by immobilized anti-CD3 mAb, although bypassing T cell receptor (TCR)/CD3 signaling led to proliferation. The poor proliferative responses of NHL-TIL could not be explained by quantitative defects in TCRzeta expression. NHL-TIL underwent marked spontaneous apoptosis in vitro with loss of approximately 50% of cells after 24 h of culture. This was associated with downregulation of the antiapoptotic Bcl-xL and Bcl-2 proteins, whereas viable NHL-TIL maintained their expression. IL-2, anti-CD3/IL-2, and manipulation of the Fas/Fas-ligand death pathway had no effect on NHL-TIL survival. Apoptosis was not due to increased cell cycling, as NHL-TIL were quiescent, nonproliferating cells. T cells from inflammatory, nonmalignant tissues gave similar functional results to NHL-TIL, suggesting the existence of factors common to the microenvironment of these diverse pathologies. Thus, the quiescent, anergic phenotype of NHL-TIL cannot be attributed solely to tumor factors, but rather is a feature of T cells from chronic inflammatory lesions.
J Clin Invest 1998 Nov 01
PMID:CD3 hyporesponsiveness and in vitro apoptosis are features of T cells from both malignant and nonmalignant secondary lymphoid organs. 980 85

Cisplatin exerts its cytotoxicity by inducing apoptosis. Similarly, all-trans retinoic acid (ATRA) causes apoptosis in certain cells. We studied the interaction of cisplatin and ATRA in human ovarian adenocarcinoma cells 2008, in human head and neck squamous carcinoma cells UMSCC10b, and in their respective cisplatin-resistant sub-lines. ATRA enhanced the cytotoxicity of cisplatin. The interaction of the drugs was synergistic in combination index-isobologram analyses (combination index >0.5 at 50% cell survival) in all of the cell lines tested. ATRA inhibited the cellular accumulation of the cisplatin analogue [3H] cis-dichloroethylenediamineplatinum(II) by 22-33% in three of four cell lines tested but did not alter the cellular content of reduced glutathione. The expression of Bcl-2 relative to Bax decreased more after combined treatment with cisplatin and ATRA than after either drug alone. The apoptotic mechanism of cell death was confirmed by demonstrating cleavage of poly(ADP-ribose)polymerase and by morphological analysis. The combined treatment with ATRA and cisplatin induced apoptosis in significantly more cells than either drug alone. We conclude that ATRA enhances the cytotoxicity of cisplatin by facilitating apoptosis in ovarian and head and neck carcinoma cells.
Clin Cancer Res 1997 Nov
PMID:all-trans retinoic acid enhances cisplatin-induced apoptosis in human ovarian adenocarcinoma and in squamous head and neck cancer cells. 981 94

Our goal was to determine the cytotoxicity of 7-OH-hydroxystaurosporine (UCN-01) as a single agent and in combination with cis-diamminedichloroplatinum(II) (CDDP) in a panel of ovarian carcinoma cells. We sought to examine the role of p53 gene function and alterations in cell cycle progression or other mechanisms of action of UCN-01 including perturbation of the apoptosis pathway mediated by NF-kappaB and Bcl-2/Bax. Cytotoxicity was determined from dose-response curves established by the Alamar blue vital dye indicator assay. Restoration of wild-type p53 in a p53 null cell line, SKOV 3, was achieved by transfection of a p53 expression vector. Cell cycle distribution was measured by fluorescence-activated cell sorting analysis of ethidium bromide-stained nuclei. Apoptosis was measured by quantitative fluorescence microscopy. NF-kappaB DNA binding activity was measured by electrophoretic mobility shift assay. Bcl-2 and Bax levels were determined by Western immunoblotting. UCN-01 was effective as a cytotoxic agent alone and in combination with CDDP in all cell lines studied, regardless of p53 status. The degree of sensitization to CDDP conferred by UCN-01, however, was found to correlate with p53 gene status. p53 wild-type cells seem to be more sensitive to the cytotoxic effects of the combination of UCN-01 + CDDP than the p53 mutant cells. This was confirmed in cells in which p53 wild-type function was restored by transfection of p53 cDNA, but these cells are also significantly more sensitive to CDDP alone. The effects of UCN-01 on cell cycle progression also appear to be p53 dependent but may not be the primary mechanism of action. The rate of apoptosis is increased 4-fold in UCN-01 + CDDP-treated cells compared to either agent alone. UCN-01 does not effect NF-kappaB DNA binding activity or Bcl-2 and Bax levels. UCN-01 enhances CDDP cytotoxicity and apoptosis in ovary cancer cells. This occurs regardless of p53 status, but wild-type p53 seems to increase the degree of sensitization.
Clin Cancer Res 1997 Nov
PMID:UCN-01 in ovary cancer cells: effective as a single agent and in combination with cis-diamminedichloroplatinum(II)independent of p53 status. 981 1

Fas is expressed in colonic epithelial cells and is also expressed in colon carcinomas, although its functional significance in the regulation of apoptosis in cells outside of the immune system remains unknown. In this study, we determined the role of Fas signaling on cellular growth of cultured colon carcinoma cells and demonstrated apoptosis induced by a cytotoxic anti-Fas monoclonal antibody (CH-11) in cells of the GC3/c1 lineage (GC3/c1, TS-, Thy4) but not in HCT116 or CaCo2 cells. Growth inhibition was detected at concentrations of CH-11 as low as 1 ng/ml, and clonogenic survival studies yielded IC50 values of 3-26 ng/ml. Cytotoxicity was inhibited by ZB4, a monoclonal antibody inhibitory to Fas signaling. In addition, the survival factor Bcl-2, which has demonstrated inconsistent protective effects against Fas signaling in other systems, was inhibitory to Fas-induced apoptosis in colon carcinoma cells after adenoviral transduction. Fas was expressed at the highest levels in TS- and Thy4 cells, which were the most sensitive cell lines to Fas-induced apoptosis. FAP-1, a protein tyrosine phosphatase that interacts with the cytosolic negative regulatory domain of Fas, was expressed in each cell line but did not correlate with sensitivity to Fas-mediated apoptosis. These data have therefore identified a functional Fas pathway in colon carcinoma cells when Fas is expressed at high levels. Hence, the role of Fas signaling in the regulation of apoptosis in colon carcinoma cells and its role in influencing the response to treatment with chemotherapeutic agents should be further explored.
Clin Cancer Res 1997 Dec
PMID:The fas signaling pathway is functional in colon carcinoma cells and induces apoptosis. 981 16

Bax and Bcl-2 are proteins that regulate programmed cell death and apoptosis. The expression of these proteins can be regulated, at least in part, by the tumor suppressor p53, but the effects of p53 are highly tissue specific. In an effort to better understand the relation between p53 and the in vivo control of the expression of Bax and Bcl-2 in adenocarcinomas of the breast, we evaluated by immunohistochemistry the expression of Bcl-2 and Bax in 149 invasive ductal carcinomas, 135 of which were chosen because of their p53 immunopositivity. The percentages of Bcl-2-immunopositive tumor cells were significantly lower in the p53-positive (median 20%) subsets as compared to the p53-negative (median 85%) subsets (P = 0. 004). Comparisons of the percentages of p53-immunopositive tumor cells with the percentages of Bcl-2- and Bax-positive cells (as continuous variables) revealed a significant inverse correlation between Bcl-2 and p53 (r = -0.41, P < 0.001) but not between Bax and p53. In the p53-positive subset, the percentages of Bax- and Bcl-2-immunopositive tumor cells were correlated positively (r = 0. 27, P = 0.002), suggesting that the expression of these genes may be co-regulated to some extent in these breast cancers. Higher percentages of Bcl-2-positive tumor cells were also associated with estrogen receptor positivity (P = 0.03), low histological tumor grade (P = 0.03), and low T stage (P = 0.02), whereas Bax immunostaining was associated only with c-erbB-2 immunopositivity (P = 0.02). Although the number of cases was small and treatment was non-uniform, preliminary correlations with clinical outcome data suggest that the prognostic significance of Bcl-2 may be enhanced by inclusion of Bax data in patients with p53-immunopositive adenocarcinoma of the breast, at least for patients with node-negative disease. Taken together, these data suggest that, despite the ability of p53 to bind directly to the Bax gene promoter, the regulation of Bax in human breast cancers does not necessarily correlate with p53 status, implying that regulation of this pro-apoptotic gene in these tumors is complex and probably influenced by several factors.
Clin Cancer Res 1997 Feb
PMID:Analysis of Bax and Bcl-2 expression in p53-immunopositive breast cancers. 1004 37

Our aim was to determine whether biological molecular markers can predict response to neoadjuvant chemoendocrine therapy in patients with early breast cancer. Ninety patients (median age 56 years; range, 28-69 years) with primary operable breast carcinoma were studied. They were treated with four 3-weekly cycles of chemotherapy with mitozantrone, methotrexate (+/- mitomycin C), and tamoxifen prior to surgery. Fine-needle aspiration was used to obtain samples from patients prior to therapy, and the following parameters were assessed: estrogen receptor (ER), progesterone receptor (PgR), p53, Ki67, Bcl-2, and c-erbB-2 measured by immunocytochemistry, and ploidy and S-phase fraction (SPF) by flow cytometry. The tumors of 78% of the subjects responded (complete response, 9%; partial response, 69%) and 22% did not (no change, 20%; progressive disease, 2%). Response rates according to disease stage and patient age were as follows: T1, 74%; T2, 79%; T3/T4, 78%; age </=50 years, 76%; >50, 79% (P = not significant). Response rates for other parameters were as follows: ER-positive, 82%, and -negative, 70%; PgR-positive, 86%, and -negative, 71%; p53-positive, 74%, and -negative, 81%; Bcl-2-positive, 85%, and -negative 61%; c-erbB-2-positive, 57%, and -negative, 93%; Ki67 high, 77%, and low, 81%; SPF high, 77%, and low, 77%; aneuploid, 71%; and diploid, 85%. Only the difference for c-erbB-2 was statistically significant (P = 0.007). A trend for higher response rates to neoadjuvant chemoendocrine therapy for tumors that were positive for ER, PgR, and Bcl-2 was observed but did not reach statistical significance. Tumors negative for c-erbB-2 had a higher response rate, which was statistically significant. In contrast, Ki67, ploidy, SPF, and p53 failed to predict for response.
Clin Cancer Res 1997 Apr
PMID:Prediction of response to neoadjuvant chemoendocrine therapy in primary breast carcinomas. 981 25

It has been proposed that diverse anticancer drugs and radiation therapy may induce a mode of cell death with the characteristics of apoptosis. Since apoptosis is under the control of several oncogenes, we analyzed the expression of the protein encoded by the proto-oncogenes bcl-2 and p53. Furthermore, we studied cell proliferation [using PC-10 mAb to proliferating cell nuclear antigen (PCNA)] and vascularization [using the CD-31 mAb and by counting intratumoral microvessel density (IMD)] using immunocytochemistry. A series of 73 patients with clinical stage II-IV squamous cell invasive carcinoma of the head and neck (H&N) were treated with concurrent chemoradiation therapy (cisplatin, 80 mg/m2, versus carboplatin, 375 mg/m2, three times every 3 weeks and a total dose of radiation therapy of 64 Gy in 6-8 weeks). We correlated the expression of these markers, determined prior to treatment, with response to the therapy and prognosis. Bcl-2 protein was expressed in 37.4% of the carcinomas (25/67 evaluable), and it was not significantly associated with any other feature studied. Forty (56. 4%) of the 71 carcinomas evaluable for p53 were p53 positive; the median IMD was 38 microvessels/field at the hot spot (range, 18-80), and the median percentage of nuclei labeled by the PC-10 mAb was 50% (range, 0-95%). In the univariate analysis, regional lymph node negativity (P = 0.016), good performance status (PS) (PS >/= 90; P = 0.044), bcl-2 positivity (P = 0.070), and low vascularization (P = 0. 085) were significantly associated with a higher probability of complete remission. In the multivariate analysis (final model), only IMD (continuous variable; P = 0.045) and PS (P = 0.017) retained significance. As far as prognosis is concerned, in the univariate analysis, patients with tumors with low histological grading (grades 1-2; P = 0.006), p53 negative (P = 0.09), bcl-2 positive (P = 0.08), and high PCNA labeling (P = 0.06) had a significantly better disease-free survival. In the multivariate analysis, only grading (P = 0.003) and p53 (P = 0.04) retained significance for disease-free survival. For overall survival, in the univariate analysis, the following markers were significantly prognostic when only deaths due to progression are considered: response to therapy (P = 0.00001), PS (P = 0.04), nodal status (P = 0.028), PCNA (P = 0.04), p53 (P = 0. 08), and grading (P = 0.01). In the multivariate analysis, only patients who achieved complete response (P = 0.00002), high PCNA values (P = 0.002), and low histological grading (P = 0.01) retained a statistically significant probability of better overall survival. Our results suggest that in this series of H&N cancer patients the markers capable of predicting response to therapy are distinct from those associated with prognosis, once the remission has been achieved. This information is potentially useful to the clinician for developing a more rational therapeutic approach for H&N cancer patients eligible for concurrent chemoradiation therapy.
Clin Cancer Res 1995 Nov
PMID:Predictive and prognostic markers in a series of patients with head and neck squamous cell invasive carcinoma treated with concurrent chemoradiation therapy. 981 34

We characterized three human brain tumor cell lines (D54, HBT-20, and HBT-28) with respect to resistance to etoposide (VP-16), a topoisomerase II-reactive drug. All three cell lines were inherently resistant to VP-16 when compared to other human cell lines, with D54 showing the greatest resistance using colony formation assays. Resistance to VP-16 has been attributed to decreased drug uptake and changes in topoisomerase II; however, drug uptake and topoisomerase II protein levels (immunoblot) were no lower in D54 than in HBT-20 and HBT-28, cell lines relatively more sensitive to VP-16. More to the point, measurement of topoisomerase II-mediated DNA cleavage of cellular DNA after treatment with VP-16 showed that the topoisomerase II in these cells was active. These data indicate mechanisms other than those attributable to decreased drug uptake or altered topoisomerase II exist for clinical resistance to VP-16. VP-16-induced DNA cleavage has been associated with apoptosis in some cell lines; however, neither DNA laddering nor morphological changes characteristic of apoptosis were detected in these cell lines after treatment with VP-16. Bcl-2 and mutant p53 were present in these cells. Either of these conditions can prevent apoptosis and could explain a dissociation between the proximal mediator of VP-16-induced cytotoxicity (topoisomerase II-DNA complex formation) and cellular death.
Clin Cancer Res 1995 Nov
PMID:Expression of topoisomerase II, bcl-2, and p53 in three human brain tumor cell lines and their possible relationship to intrinsic resistance to etoposide. 981 36

2-Chloro-2'-deoxyadenosine, (CldAdo) resistance was developed in the W1L2 human B lymphoblastoid (resistance factor, 160) and L1210 murine leukemia (resistance factor, 605) cell lines by continuous exposure to CldAdo. Cross-resistance studies showed that while the variant lines generally retained sensitivities to 9-beta-D-arabinofuranosyladenine (in the presence of 2'-deoxycoformycin), hydroxyurea, and Adriamycin, both were highly cross-resistant to 1-beta-D-arabinofuranosylcytosine (ara-C), 2', 2'-difluorodeoxycytidine, and 9-beta-D-arabinofuranosyl-2-fluoroadenine. Measurement of both phosphorylating and degrading enzyme activities demonstrated that initial phosphorylation of CldAdo and 2'-deoxycytidine were severely impaired in cell extracts from the resistant lines, whereas adenosine kinase activity remained unaffected and there was no apparent increase in cytoplasmic deoxynucleotidase activity using dCMP as substrate. Since previous reports indicated that either overexpression of Bcl-2 protein following bcl-2 transfection into cells resulted in, or high dCTP pools contributed to, ara-C resistance in experimental cell models, both of these parameters were assessed and found not to contribute to CldAdo resistance in the murine leukemia and human B lymphoblastoid cells. These studies show that a deficiency of 2'-deoxycytidine kinase activity is a major determinant of CldAdo acquired resistance in both the murine and human lymphoid lines.
Clin Cancer Res 1995 Apr
PMID:2'-Deoxycytidine kinase deficiency is a major determinant of 2-chloro-2'-deoxyadenosine resistance in lymphoid cell lines 981 96


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