Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The significance of apoptosis in relation to the development and progression of prostate cancer remains largely undefined. bcl-2 is an oncogene that functions by overriding apoptosis. bcl-2 expression was localized to the basal epithelial cells in the normal human prostate with the use of immunohistochemistry. Androgen-dependent and androgen-independent prostate carcinomas were evaluated immunohistochemically for bcl-2 expression. bcl-2 was undetectable in 13 of 19 cases of androgen-dependent cancers. In contrast, androgen-independent cancers displayed diffuse, high levels of bcl-2 staining (P < 0.01). In rats, steady-state levels of bcl-2 mRNA, assessed by S1 assays, reached maximum levels 10 days following castration. Addition of exogenous testosterone with, or without, flutamide demonstrated that the increased bcl-2 mRNA resulted from androgen ablation. Our findings indicate that bcl-2 expression is augmented following androgen ablation and is correlated with the progression of prostate cancer from androgen dependence to androgen independence.
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PMID:Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. 145 83

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.
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PMID:Combination adriamycin and suramin induces apoptosis in bcl-2 expressing prostate carcinoma cells. 762 22

beta-Lapachone, a plant product, has been shown to be a novel inhibitor of DNA topoisomerase I, with a mode of action different from camptothecin and a chemical structure distinct from those of current anti-cancer drugs. We observed that beta-lapachone, at concentrations of less than 8 microM, induces cell death with characteristics of apoptosis in human prostate cancer cell lines. This effect of beta-lapachone was also observed in a human promyelocytic leukemia cell line (HL-60). beta-Lapachone-induced apoptosis is independent of p53 expression, and ectopic overexpression of bcl-2 did not confer significant resistance to beta-lapachone. Among other human carcinoma and adenoma cell lines tested, human breast and ovary carcinoma showed sensitivity to the cytotoxic effect of beta-lapachone without manifesting signs of apoptosis. These results suggest that beta-lapachone is a potential compound to be added to cancer chemotherapy, particularly for prostate cancer.
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PMID:Induction of apoptosis by beta-lapachone in human prostate cancer cells. 764 Nov 81

Normal (nonneoplastic) human prostatic secretory epithelial cells do not express the bcl-2 protein. However, a recent immunohistochemical survey of neoplastic human prostate tissues showed that a fraction of primary untreated prostate adenocarcinoma cells expressed this apoptosis-suppressing oncoprotein at significant levels (Colombel et al., Am. J. Pathol., 143: 390-400, 1993). Additionally, a number of hormone-refractory prostatic adenocarcinomas obtained from hormonally-treated patients (subsequent to surgical or drug castration therapy) were examined and were found to be uniform in their elevated expression of bcl-2 oncoprotein. The results of this preliminary survey imply that bcl-2 expression distinguishes a subgroup of primary human prostate cancers and that the expression of this protein might be a factor enabling prostate cancer cells to survive in an androgen-deprived environment. The current study was undertaken to determine the degree to which overexpression of bcl-2 can protect human prostate cancer cells from apoptotic stimuli in vitro and in vivo. Human prostate cancer cells (LNCaP) were transfected with a neomycin-selectable eucaryotic expression vector containing cDNA encoding human bcl-2. Transfected clonal variants that express bcl-2 protein (LNCaP/bcl-2) were unaltered with regard to their basal growth rate in 10% serum-containing medium, or with regard to their expression of the differentiated human prostate cell gene products prostate-specific antigen or androgen receptor protein. The bcl-2-transfected clones were altered, however, with regard to their growth rate in charcoal-stripped serum lacking dihydrotestosterone. Additionally, in contrast to the parental or control-transfected cell lines, LNCaP/bcl-2 cells were highly resistant to a variety of apoptotic stimuli in vitro including serum starvation and 10 nM phorbol ester (phorbol 12-myristate 13-acetate) supplementation of the medium. Lastly, the overexpression of bcl-2 by these prostate cancer cells altered their tumorigenic potential in a nude mouse assay. s.c. injections of 10(6) LNCaP/bcl-2 cells into male nude mice resulted in earlier and larger tumor formation compared to an equivalent injection of parental or control-transfected LNCaP cells. When these variant cell lines were injected into castrated male nude mice, only the LNCaP/bcl-2-transformed cells gave rise to tumors. Moreover, LNCaP/bcl-2 tumors grown in intact male nude mice were refractory to the growth-inhibiting effects of castration demonstrated by parental LNCaP cells. Data obtained in this study demonstrate that the bcl-2 oncoprotein can protect prostate cancer cells from apoptotic stimuli in vitro and suggest that such protection correlates with the ability to form hormone-refractory prostate tumors in vivo.
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PMID:Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. 767 Dec 57

We describe an in vitro model for prostate cancer treatment that suggests a potential benefit for combined androgen ablation and cytotoxic chemotherapy. Androgen treatment of the LNCaP hormone-dependent human prostate cancer cell line induces increased expression of the BCL-2 protein. Increased levels of this protein are known to mediate inhibition of apoptosis. LNCaP cells, however, did not undergo apoptosis in response to androgen withdrawal. Etoposide exerts its cytotoxicity on LNCaP and other cells by inducing apoptosis. In vitro etoposide cytotoxicity was diminished 83% in the presence of either 10(-8) M dihydrotestosterone or 10(-9) M R1881 in LNCaP cells. The interaction between androgen and etoposide was mediated through the BCL-2 protein, since bcl-2 antisense oligonucleotides blocked the protective effect of androgens on etoposide cytotoxicity.
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PMID:Androgens induce resistance to bcl-2-mediated apoptosis in LNCaP prostate cancer cells. 785 Jul 82

The progression of prostatic adenocarcinoma from localized disease to metastatic carcinoma appears to be a multi-step sequence. The expression of common oncogenes/oncosuppressor genes and the mediating effect of neuroendocrine tumor cells may play a role in this progression. The expression of the more frequently investigated oncogenes/oncosuppressor genes (p53, c-myc, c-erbB-2, bcl-2) and the presence of neuroendocrine cells were assessed in prostatic cancer tissue from patients with localized and metastatic cancer. These oncogenes/oncosuppressor genes were evaluated according to tumor stage and grade and their relationship to one another. Grade was not related to any of the oncogene markers or to the presence of neuroendocrine cells. Advancing stage was associated with a significant increase in p53 expression, while other markers remained constant in all stages. Neuroendocrine cells, p53, c-myc, c-erbB-2 and bcl-2 were rarely co-expressed at any stage of prostate cancer.
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PMID:Immunohistochemical detection of oncogene proteins and neuroendocrine differentiation in different stages of prostate cancer. 853 88

Hormonal manipulation of cancer is no longer confined to the use of effective antiestrogen therapy for breast cancer or surgical or hormonal castration for prostate cancer. A broader acknowledgment of the potential of different hormonal ligands to evoke cell cycle arrest to prevent the progress of neoplastic transformation, and even to elicit active cell death, has expanded the concept of hormonal therapy. The use of retinoids and deltanoids in conjunction with antiestrogens and antiandrogens is progressing into clinical trials. The use of glucocorticoids in conjunction with cyclic AMP may enhance apotosis induction. The use of antiandrogens in conjunction with cytotoxic therapy may diminish the risk of bcl-2-mediated resistance in prostate cancer. Innovative use of sequential and synergistic hormonal manipulations based on an expanding understanding of transcriptional regulation promises to advance this science.
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PMID:Recent advances in hormonal therapy for cancer. 854 8

Treatment of prostate cancer cell lines expressing bcl-2 with taxol induces bcl-2 phosphorylation and programmed cell death, whereas treatment of bcl-2-negative prostate cancer cells with taxol does not induce apoptosis. bcl-2 phosphorylation seems to inhibit its binding to bax since less bax was observed in immunocomplex with bcl-2 in taxol-treated cancer cells. These findings support the use of the anticancer drug taxol for the treatment of bcl-2-positive prostate cancers and other bcl-2-positive malignancies, such as follicular lymphoma.
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PMID:Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. 864 Aug 9

Bcl-2 expression is associated with the progression of prostate cancer from androgen-dependence to androgen-independence. Bcl-2 is an integral membrane protein which localizes to mitochondria, endoplasmic reticulum, and the nuclear envelope. Using spectrofluorometry and laser confocal microscopy, the ability of bcl-2 to modulate intracellular Ca2+ was examined in the Dunning G prostate carcinoma cell line following apoptosis induction by adriamycin. Adriamycin and thapsigargin, an endoplasmic reticulum Ca2+-pump inhibitor, were effective inducers of apoptosis in control, but not bcl-2 transfected, cells. Treatment with adriamycin was accompanied by a sustained rise in cytoplasmic Ca2+ in control and bcl-2 transfected cells. An increase in intranuclear Ca2+ was observed in control cells only. Apoptosis induction by thapsigargin was associated with an increase in cytoplasmic Ca2+ in control cells that was not detected in the resistant bcl-2 transfectants. Ca2+ was excluded from nuclei isolated from bcl-2 expressing cells, but was sequestered in control nuclei, following the addition of ATP. These findings suggest that bcl-2 may regulate levels of intranuclear Ca2+ independently of cytosolic Ca2+ levels. The ability of bcl-2 to modulate, directly or indirectly, sustained increases in both cytosolic and intranuclear Ca2+ may provide a common basis for bcl-2 function in different subcellular compartments.
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PMID:Apoptosis suppression by bcl-2 is correlated with the regulation of nuclear and cytosolic Ca2+. 864 65

The state of the art concerning major biological phenomenons of importance for current research on urological cancers is first briefly presented, followed by notes on the more outstanding presentations in this field. These notes are organized in a synthetic fashion, in order to point to the meaning of the hypotheses and findings presented, when taken together, as they pertain to the understanding of the mechanisms at play in urological cancers, as we see them in 1995. Some concepts seem to have now reached a point where we can expect to see some applications in a not so distant future: in prostate cancer, it is confirmed that the machinery of apoptosis is functional even in the hormone-insensitive cells, suggesting that its enhancement might be useful in these often difficult situations; techniques to detect circulating malignant cells, which have been greatly refined (RT-PCR of PSA and PSM), are now extremely sensitive and may prove unvaluable in providing intermediate end points to compare the relative efficacy of treatment regimens in clinical trials; the symposium on prostate cancer screening by PSA dosage was an excellent opportunity to review extensively the data available on this topic, but -as expected- it could not decide on some essential issues; in bladder tumors, data on the expression of adhesion molecules (CD44 variant) are still preliminary, but some provocative observations have been reported (presence on mature ARN, only in bladder cancer cells, of intronic sequences that have not been excised); in renal cell cancer, a considerable amount of knowledge has accumulated on the von Hippel-Lindau gene, a putative anti-oncogene, and work is in progress to define the function of its protein; finally, pathways essential to understanding and treating cancer have been dissected, particularly the apoptosis-proliferation network, and the involvement in it of p53, Waf-1 and the bcl-2 gene family cascade.
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PMID:[The annual meeting of the American Association for Cancer Research (AACR), Toronto (Ontario), 18-22 May 1995]. 867 62


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