Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the modulation of radio- and chemoresistance by caffeine and mechanisms of resistance in human leukemic cell lines and mononuclear cells from 18 leukemic patients. Caffeine synergistically potentiated cytotoxicity and apoptosis induced by ionizing radiation or carboplatin (CPt), but attenuated induction of apoptosis by daunorubicin (DNR) in KG-1a cells. Since caffeine released irradiated as well as DNR-treated KG-1a cells from G2M cell cycle arrest and CPt-treated cells from S-phase arrest, this release does not fully explain the different effects of caffeine. Caffeine synergistically reduced the level of the apoptosis inhibitor glutathione after irradiation or CPt treatment. In contrast, treatment with DNR plus caffeine diminished glutathione levels to a lesser extent than DNR alone. We conclude that the effect of caffeine on glutathione depletion represents a mechanism of action by which caffeine can modulate apoptosis. Caffeine increased CPt cytotoxicity in K562 cells and its doxorubicin-resistant subline (K562/ADM), but little effect was seen in HL-60 cells or mononuclear cells from leukemic patients. Multivariate cluster analysis revealed an association of CPt resistance with the expression of c-Fos, c-N-Ras, and p53 oncoproteins and with proliferative activity (S-phase of cell cycle), but not with Bcl-2 expression.
J Cancer Res Clin Oncol 1995
PMID:Expression of apoptosis-related oncoproteins and modulation of apoptosis by caffeine in human leukemic cells. 759 28

The effect of co-inoculation of basement membrane matrix, Matrigel and two human breast cancer cell lines, BT-474 and SK-BR-3, was tested in immune-deficient mice. Both cell lines strongly overexpress c-ErbB-2 protein, whereas only BT-474 is reported to be oestrogen receptor positive. Co-inoculation of Matrigel and BT-474 cells but not of Matrigel and SK-BR-3 cells resulted in tumour formation in bg-nu-xid mice. Oestrogen supplementation greatly enhanced tumorigenicity, but did not seem to be an absolute requirement. In vivo, BT-474 cells grow as a poorly differentiated adenocarcinoma with a doubling time of 9.4 +/- 1.1 days after inoculation into the neck region. A high proliferative activity appears to be compensated by a relatively high rate of cell loss, as BT-474 tumours contain many cells with the typical morphology of apoptotic cell death. Wild-type p53, known to participate in the induction of apoptosis, is absent from the tumours, whereas Bcl-2, known to inhibit apoptosis, is expressed at intermediate levels. BT-474 tumours tend to metastasise to the regional lymph nodes and are capable of forming micrometastatic lesions in the lung. Flow cytometrical analysis of DNA ploidy demonstrated no change in tumours compared with the cell line. Immunohistochemical and flow cytometrical detection of a number of hormone and growth factor receptors, transcription factors, cell adhesion molecules and proteins involved in proliferation and cell death demonstrated no major changes in ploidy and phenotype of tumours compared with the cell line. High expression of the cell-surface molecules c-ErbB-2 and episialin make it a potentially useful model for research in immune therapy.
Br J Cancer 1995 Jul
PMID:Outgrowth of BT-474 human breast cancer cells in immune-deficient mice: a new in vivo model for hormone-dependent breast cancer. 759 56

The control of cell survival is of central importance in tissues with high cell turnover such as the lymphoid system, and its disruption may be a critical step in tumorigenesis. Genes homologous to bcl-2, the oncogene implicated in human follicular lymphoma, play a key role in regulating physiologic cell death (apoptosis). Bcl-2 and its relatives bcl-x and bax encode intracellular membrane-bound proteins that share homology in three domains with a wider family of viral and cellular proteins. The Bcl-2 and Bcl-x proteins enhance the survival of lymphocytes and other cell types but do not promote their proliferation. High levels of Bax or of a smaller Bcl-x variant antagonize the survival function of Bcl-2. The mechanism by which Bcl-2 promotes cell survival remains unknown, but it appears to require association with Bax. Bcl-2 may combat the action of cysteine proteases thought to trigger apoptosis. Bcl-2 is not essential for embryogenesis or lymphoid development. However, upregulation of Bcl-2 appears to be the normal mechanism for positive selection of developing lymphocytes, and its continued expression is critical for survival of mature peripheral B and T cells. Constitutive expression of Bcl-2 does not abrogate deletion of self-reactive lymphocytes, nor disturb T lymphoid homeostasis; however, it substantially increases the pool of mature noncycling B cells. The risk of B lymphoid tumors is also enhanced, probably because Bcl-2 can countermand the apoptotic action of other oncoproteins such as Myc. Expression in tumors of bcl-2 and other cell survival genes may constitute a major barrier to the success of genotoxic cancer therapy.
 ...
PMID:Regulation of lymphocyte survival by the bcl-2 gene family. 761 33

Bcl-2 expression has been associated with progression of prostate cancer from androgen-dependence to androgen-independence and may contribute to the relative drug-resistant phenotype typically observed in androgen-independent prostate cancer. Dunning-G rat prostate cancer cells transfected with a bcl-2 expression vector demonstrated resistance to apoptosis induced by adriamycin and, to a lesser extent, suramin. Use of adriamycin and suramin in combination, however, circumvents this bcl-2 associated drug resistance. Our findings indicate that combination drug actions may induce apoptosis in resistant malignant cell types with defective apoptotic pathways.
Cancer Lett 1995 Jul 13
PMID:Combination adriamycin and suramin induces apoptosis in bcl-2 expressing prostate carcinoma cells. 762 22

During the last decades, major medical advances have been made in the understanding of cancer biology and led to the appearance of new diagnostic tools and development of innovative therapeutics. Some basic concepts in molecular medicine, oncogenes and tumour-suppressor genes are reviewed. Special topics are devoted to Ras, erbB2, p 53 and characteristical gene rearrangements, such as bcr-abl, RARA-PML, VDJ, bcl2-IgH. The greater knowledge of the molecular etiology of cancer will contribute to disease screening, diagnosis, staging and therapy, detection of residual or recurrent disease, and development of new treatments, such as gene therapy or drugs targeted to oncogene products.
 ...
PMID:[Contribution of molecular and genetic biology in oncology]. 762 61

t(14;18) is the most common translocation in human lymphoid malignancy and results in bcl-2 overexpression. Bcl-2 blocks apoptosis and constitutes the initial member of a new category of oncogenes, ie, regulators of cell death. Bcl-2-Ig transgenic mice develop follicular hyperplasia and progress to malignant B-cell lymphoma. To assess the oncogenic potential of bcl-2 in the T-cell lineage, a cohort of 68 lckpr-bcl-2 transgenic mice and 56 control littermates were monitored for signs of malignancy over a 24-month period. Eighteen (26%) lckpr-bcl-2 mice developed diffuse, predominantly large-cell lymphomas at a mean age of 18 months. In contrast, only one nontransgenic control mouse developed lymphoma. CD3 surface expression and clonal T-cell receptor beta rearrangements support the T-lineage classification of these neoplasms. lckpr-bcl-2-enforced lymphomas are predominantly CD4+CD8-, consistent with a mature peripheral T-cell phenotype. These data provide support for the thesis that violation of homeostasis through the repression of cell death can be a primary mechanism of tumorigenesis in multiple lineages.
 ...
PMID:Peripheral T-cell lymphoma in lckpr-bcl-2 transgenic mice. 763 29

Recent studies have shown that the Bcl-2 protein suppresses programmed cell death or apoptosis induced by a variety of stimuli including chemotherapeutic drugs. Because estrogen promotes the survival of estrogen-dependent breast cancer cells in vivo, we investigated whether estrogen might regulate levels of Bcl-2 gene expression in an estrogen-responsive human breast cancer cell line. Estrogen receptor-positive MCF-7 human breast cancer cells cultured in the presence of estrogen express the 8.5-kb Bcl-2 mRNA transcript. Depletion of estrogen from the medium results in loss of expression of the mRNA, whereas reexposure to estrogen markedly induces the Bcl-2 transcript. The changes in Bcl-2 mRNA are paralleled by changes in Bcl-2 protein levels. Estrogen-induced increases in Bcl-2 are significantly inhibited by inclusion of the pure antiestrogen ICI 164,384 in the medium. The Bax protein that heterodimerizes with Bcl-2 and promotes cell death is expressed in MCF-7 cells grown in the presence of estrogen and is unaffected by culture in estrogen-free medium. Estrogen depletion doubles the sensitivity of MCF-7 cells to the cytotoxic effects of Adriamycin compared with cells cultured in medium supplemented with estrogen, consistent with a decrease in the Bcl-2 levels. MCF-7 cells treated simultaneously with estrogen and ICI 164,384 exhibit markedly lower resistance to Adriamycin compared with cells treated with estrogen alone. In the absence of estrogen, MCF-7 cells transfected with Bcl-2 expression plasmids display a marked increase in resistance to Adriamycin. In the presence of estrogen, MCF-7 cells expressing Bcl-2 antisense transcripts are rendered twice as sensitive to acute Adriamycin cytotoxicity as a control clone. We conclude that estrogen can promote resistance of estrogen receptor bearing human breast cancer cells to chemotherapeutic drugs through a mechanism that involves regulation of the Bcl-2 proto-oncogene.
Cancer Res 1995 Sep 01
PMID:Estrogen promotes chemotherapeutic drug resistance by a mechanism involving Bcl-2 proto-oncogene expression in human breast cancer cells. 764 Dec 10

Bcl-2 has been shown to inhibit apoptosis induced by several anticancer agents and to cause a dissociation between etoposide (VP-16)-induced protein-cross-linked DNA strand breaks and VP-16-induced cell death. We suggested previously that VP-16-induced cytotoxicity is mediated by a series of events leading from cleavable complex formation to aberrant DNA recombination, as measured by sister chromatid exchange (SCE) and Southern blot analysis of the hypoxanthine phosphoribosyl transferase (hprt) gene mutations. To further evaluate this hypothesis and to determine whether Bcl-2 could affect any steps leading to the aberrant DNA recombination process, we stably transfected an expression vector containing human Bcl-2 cDNA into V79 Chinese hamster cells. This transfection resulted in overexpression of the Bcl-2 gene product. We subsequently quantitated the relationship between VP-16-induced cytotoxicity, DNA strand breaks, SCE, and mutant frequency at the hprt locus in these Bcl-2-overexpressing cells. Two independent Bcl-2-overexpressing cell lines, BCL2/2 and BCL2/4, showed 3-5 times higher survival at 15 microM VP-16 compared with parental V79 cells or control NeoR cells that were obtained by transfecting V79 cells with the expression vector containing the G-418 resistance gene only. DNA single-strand breaks induced by VP-16 were similar in parental V79, control NeoR, BCL2/2, and BCL2/4 cells. In contrast, VP-16 induced significantly less SCE in Bcl-2-overexpressing cell lines compared with parental V79 and control NeoR cells. The SCE/chromosome induced by 15 microM VP-16 were 0.65, 0.42, 0.09, and 0.10, respectively, in V79, NeoR, BCL2/2, and BCL2/4. In addition, there was an excellent correlation between VP-16-induced SCE and cytotoxicity in all cell lines. Furthermore, VP-16-induced mutant frequencies at the hprt locus were 5-10 times less in BCL-2/2 and BCL-2/4 cells than those observed in the V79 or NeoR control cells. These results indicate that overexpression of Bcl-2 is associated with reduction in VP-16-induced genetic recombination, mutation, and cytotoxicity. Moreover, they suggest that Bcl-2 modulates cytotoxicity of VP-16 between cleavable complex formation and subsequent induction of DNA recombination events. Thus, our results provide important support for the hypothesis that VP-16-induced cytotoxicity is associated with aberrant recombination events, including gene deletions and rearrangements.
Cancer Res 1995 Sep 15
PMID:Inhibition of etoposide (VP-16)-induced DNA recombination and mutant frequency by Bcl-2 protein overexpression. 766 76

Bax is a homologue of Bcl-2 that promotes apoptosis. Bax protein levels were assessed by immunohistochemical methods in primary tumors derived from 119 women with metastatic breast cancer. These patients had received combination chemotherapy either with a once a month dosage schedule or in 4 weekly divided doses. The BAX immunostaining results were retrospectively compared with overall survival, time to tumor progression (TTP), and response, as well as several laboratory markers. Normal breast epithelium and in situ carcinomas immunostained positively for Bax. Marked reductions in Bax immunostaining were observed in 40 (34%) of 119 evaluable tumors. Reduced Bax correlated with shorter overall survival (median, 8.1 versus 15.7 months; P = 0.04), faster TTP (median, 2.0 versus 6.3 months; P = 0.009), and failure to respond (complete response, partial responses; 6% versus 42%, P = 0.01) in the subgroup of patients who received divided dose therapy. Reduced Bax immunostaining was not significant in the monthly dose group. When the two groups were combined, however, reduced Bax was significantly correlated in univariate analysis with failure to respond (21 versus 43% achieving complete response or partial response; P = 0.02), faster TTP (median, 3.7 versus 9.0 months; P = 0.02), and shorter survival (median, 10.7 versus 17.1 months; P = 0.04). Bax immunostaining was not significantly correlated with tumor histology, S-phase fraction, aneuploidy, p53 HER2, or cathepsin D, but was positively associated with Bcl-2 (P = 0.005). In multivariate analysis (Bax, tumor grade, and treatment group), reduced Bax was strongly associated with faster TTP (P approximately equal to 0.009) and shorter survival (P approximately equal to 0.001). Although highly preliminary, the finding suggest that loss of Bax immunostaining represents a novel prognostic indicator of poor response to chemotherapy and shorter survival in women with metastatic breast cancer, and raise the possibility that the subgroup of women with Bax-negative tumors may benefit from more aggressive therapy.
Cancer Res 1995 Oct 01
PMID:Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. 767 Dec 62

We have established three lymphoma cell lines, HF-1 from one follicular lymphoma (FL) patient, and HF-4 and HF-9 from another. All cell lines carry the characteristic t(14;18) chromosomal translocation and express constitutively the bcl-2 gene product (Bcl-2 protein). Cross-linking of their surface membrane Igs (sIgs) with relevant antibodies triggers a vigorous calcium signal in all three lines but only HF-1 is induced to apoptosis. Treatment with anti-Ig arrests the proliferation of HF-1 within 6-12 h, nucleosomal DNA fragmentation is evident in 18 h and a morphologically complete apoptosis is seen in 24-48 h. While bcl-2 was expressed at equal levels in all lines, the apoptosis-sensitive HF-1 line displayed a much lower expression of c-myc than seen in the apoptosis-resistant line. This finding challenges the concept that expression of bcl-2 per se renders resistance to apoptosis but that the balance between the expression of bcl-2 and c-myc may dictate the outcome of sIg cross-linking. HF-1 is a unique, phenotypically mature human B cell line expressing surface IgG. This cell line offers a new tool for investigations on apoptosis and induction of tolerance in mature B lymphocytes. Our results suggest that some FLs may be amenable to anti-cancer treatment based on anti-sIg antibody induced apoptosis.
 ...
PMID:Cross-linking of surface IgG induces apoptosis in a bcl-2 expressing human follicular lymphoma line of mature B cell phenotype. 769 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>