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)

Abnormalities in genes of the apoptotic pathway might contribute to survival in prostatic cancer (PCa) cells after radiation therapy (RT). We investigated the immunohistochemical expression of the products of the p53, p21WAF1, and bcl-2 genes in pre-RT and post-RT biopsy specimens from 38 patients with locally advanced PCa. All of the 38 patients underwent a uniform protocol of RT with or without neoadjuvant hormonal therapy. Immunohistochemical staining for expression of the products of the p53, p21WAF1, and bcl-2 genes was performed on material from pre-RT and post-RT specimens. Sufficient tissue for analysis was available from 25 of the pre-RT and 38 of the post-RT biopsy specimens. In benign prostatic epithelium, RT resulted in expression of p53 (2 [8%] of 25 pre-RT specimens vs. 15 [71%] of 21 post-RT specimens; P < .001) and increased expression of bcl-2 (1 [5%] of 18 pre-RT vs. 18 [86%] of 21 post-RT; P < .001). There was no change in the expression of p21WAF1 (1 [4.5%] of 22 pre-RT vs. 4 [17%] of 23 post-RT; P = NS). Post-RT specimens were positive for PCa in 24 (63%) of 38 cases. In the PCa tissue, p53 expression was seen in 10 (42%) of 24 pre-RT and 12 (63%) of 19 post-RT samples (P = NS). A significant upregulation of p53 was seen in the subgroup of patients who did not receive neoadjuvant hormonal therapy (9 [82%] of 11 vs. 3 [38%] of 8; P = .05). No significant change in p21WAF1 (5 [21%] of 24 vs. 5 [33%] of 15; P = NS), or bcl-2 (4 [18%] of 22 vs. 3 [21%] of 14; P = NS) expression was detected. There was no significant correlation between immunohistochemical expression of apoptosis-related markers and treatment failure. We concluded that RT induced upregulation of the bcl-2 and p53 gene products in benign prostatic tissue and that this likely reflected a protective mechanism in genetically unaltered epithelium. Increased p53 expression in PCa was only seen in patients without neoadjuvant hormonal treatment, indicating that the cancer cells with abnormal p53 were at least partially protected from RT-induced cell death.
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PMID:Expression of bcl-2, p53, and p21 in benign and malignant prostatic tissue before and after radiation therapy. 975 70

Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the formation of prostaglandins and other eicosanoids from arachidonic acid, is constitutively expressed in LNCaP human prostate cancer cell line. To evaluate the potential role of COX-2 in prostate cancer, LNCaP cells were treated with NS398, a selective COX-2 inhibitor, and the effects on cell viability and apoptosis were determined. NS398 treatment induced apoptosis in LNCaP cells in a time- and dose-dependent fashion. Treatment with 100 microM NS398 caused a down-regulation in bcl-2 protein expression, followed by chromatin condensation, chromosomal DNA fragmentation, and changes in nuclear morphology detected by 4,6-diamidino-2-phenylindole staining, DNA fragmentation assay, and terminal deoxynucleotidyl transferase-mediated UTP-biotin nick end-labeling assay. In contrast, NS398 treatment had no effect on either cell viability or nuclear function and morphology in human fetal prostate fibroblasts. These results demonstrate that NS398 induces apoptosis in LNCaP cells but not in human fetal prostate fibroblasts, and that this induction is associated with a decreased level of bcl-2 protein.
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PMID:NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down-regulates bcl-2 expression in LNCaP cells. 976 45

The chemotherapeutic agent paclitaxel disrupts microtubule dynamics causing mitotic arrest, which leads to cell death. However, in paclitaxel-resistant tumor cells, treatment with paclitaxel induces abnormal progression through prophase resulting in a multimininucleated phenotype. Multimininucleation and subsequent polyploidization have been correlated with paclitaxel resistance. Paclitaxel treatment of HeLa cells resulted in cell death via typical activation of the apoptotic machinery, whereas treatment of the relative paclitaxel-resistant prostate cancer cell line PC-3 induced an attenuated caspase activation and multimininucleation. The multimininucleated phenotype could be mimicked in HeLa cells treated with paclitaxel and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), a peptide caspase inhibitor. Interestingly, we observed no discernible difference in the pattern of cdc-2 kinase activation or phosphorylation of bcl-2-like proteins in PC-3 and HeLa cells treated with paclitaxel, which demonstrated that these molecules could not be used as indicators for the degree of caspase activation. In this study, we establish a connection between relative paclitaxel resistance, caspase attenuation/inhibition, and the multimininucleated phenotype.
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PMID:Paclitaxel-associated multimininucleation is permitted by the inhibition of caspase activation: a potential early step in drug resistance. 978 20

bcl-xL is an antiapoptotic protein that shares sequence homology with bcl-2 and seems to convey chemoresistance in many human tumor cell lines. bcl-xL protein is expressed at a 3-fold higher level in PC-3 cells than it is in LNCaP cells. Taxol causes apoptosis in both these cell lines, as measured by the formation of DNA ladders and by the observation of typical cellular morphological changes (chromatin condensation and nuclear fragmentation) after 4', 6-diamidino-2-phenylindole staining. Overexpression of bcl-2 in LNCaP cells did not prevent Taxol-induced apoptosis. Treatment of LNCaP cells with 10 nm Taxol led, after 24 h, to relatively specific and almost total down-regulation of bcl-xL protein in the absence of alteration of bax, bak, or bcl-2 levels. This change was paralleled by a similar decrease in the level of bcl-xL mRNA, as demonstrated by reverse transcription-PCR. The level of glyceraldehyde-3-phosphate dehydrogenase mRNA was not changed. In PC-3 cells, 48 h were required for both maximal bcl-xL protein down-regulation and cellular apoptosis. In contrast, treatment of LNCaP cells with estramustine induced apoptosis, but this was not associated with any change in the intracellular level of bcl-xL or bax protein. Instead, relatively specific 2-fold up-regulation of the proapoptotic protein bak was observed. In PC-3 cells, cellular apoptosis induced by estramustine was bak independent. These results augment our understanding of the importance of bcl-xL in prostate cancer and suggest that appropriate manipulation of cytotoxic chemotherapeutic agents may favorably alter the balance between pro- and antiapoptotic proteins in this tumor.
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PMID:Taxol and estramustine-induced modulation of human prostate cancer cell apoptosis via alteration in bcl-xL and bak expression. 981 95

Androgen ablation has been an effective treatment in patients with advanced prostate cancer. However, most treated patients develop hormonally resistant disease and do not respond to conventional chemotherapy. Immunotherapy against prostate cancer is an alternative approach in overcoming hormonal/drug-resistant prostate cancer. Cytotoxic immune lymphocytes kill target cells via the perforin/granzyme and the Fas-ligand (Fas-L) pathways. We hypothesize that tumor cells respond poorly to immunotherapy by developing resistance to killing by the Fas-L mechanism. This study investigated whether prostate tumor cells are sensitive to Fas-mediated killing. The human prostate carcinoma cell lines DU145, PC-3, and LnCAP were examined for their sensitivity to killing and apoptosis by the Fas-L agonist anti-Fas antibody and CTLs. All three lines moderately expressed the Fas antigen on the cell surface; however, all three lines were relatively resistant to cytotoxicity mediated by anti-Fas (CH-11) antibody. Pretreatment of DU145 and PC-3 with subtoxic concentrations of drugs followed by anti-Fas antibody resulted in synergistic cytotoxicity and apoptosis, whereas only an additive effect was obtained with LnCAP. Chemosensitization with drugs and anti-Fas was completely blocked by the addition of neutralizing anti-Fas antibody. The murine CTL hybridoma, PMMI, which kills only via the Fas-L pathway, was able to kill chemosensitized PC-3 and DU145 but not LnCAP cells. Furthermore, this cytotoxicity was blocked by anti-Fas neutralizing antibody. Chemosensitization of PC-3 and DU145 prostate tumor cells was not due to up-regulation of Fas-receptor antigen expression. Treatment of tumor cells with cisplatin did not down-regulate the antiapoptotic genes bcl-2, FAP-1, and c-myc. Further, there was no induction by cisplatin of Fas-L on the tumor cells, thus ruling out Fas/Fas-L-mediated autologous killing. These findings demonstrate that pretreatment of drug-resistant/CTL-resistant prostate DU145 and PC-3 tumor cells with subtoxic concentrations of certain chemotherapeutic drugs sensitizes the tumor cells to Fas-mediated cytotoxicity. These findings suggest that chemosensitization of tumor cells should optimize the response to immunotherapeutic interventions in the treatment of hormone-resistant/drug-resistant prostate cancer.
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PMID:Chemosensitization of human prostate carcinoma cell lines to anti-fas-mediated cytotoxicity and apoptosis. 981 72

The frequency of bcl-2 protein expression was evaluated using immunocytochemical staining during the progression of human and rat prostate cancer from an androgen-sensitive nonmetastatic to an androgen-independent metastatic phenotype. Previous studies (A. S. Shabaik et al., J. Urol. Pathol., 3: 17-27, 1995) demonstrated that 0 of 20 high-grade prostatic intraepithelial neoplasias and only 3 (7%) of 41 pathologically localized stage B human prostatic cancers had detectable bcl-2 staining. In the present study, 5 (17%) of 30 lymph node metastases from pathologically disseminated D1 disease and 14 (52%) of 27 bone metastases from pathologically disseminated D2 disease expressed detectable bcl-2 protein. These data demonstrate that there is a statistically significant (P < 0.05) association between expression of bcl-2 and the progression of human prostatic cancer cells to a metastatic phenotype. Such bcl-2 expression is not absolutely required, however, for either androgen independence or metastatic ability by human prostatic cancer cells. Likewise, within a series of eight distinct Dunning R3327 rat prostatic cancer sublines, which differ widely in their progressional state, there is also a significant association (P < 0. 05) between bcl-2 expression and progression (four of six androgen-independent rat sublines expressed bcl-2 protein). Again in this rodent system, bcl-2 expression is not an absolute requirement for either androgen independence or metastatic ability. For example, the androgen-independent highly metastatic Dunning AT-3 subline, while expressing bax protein, does not express bcl-2 protein. If such AT-3 cells are genetically engineered to express bcl-2, these expressing cells are now cross-resistant to a variety of mechanistically diverse noxious insults (e.g., viral infection or exposure to antimetabolites, alkylating agents, or agents which elevate the intracellular free Ca2+). The ability of bcl-2 to inhibit the programmed death of AT-3 cells induced by these agents involves a late step in the death process, since the early induction of expression of a series of genes associated with apoptosis is not impaired by bcl-2 expression. These data demonstrate that the development of androgen independence and/or metastatic ability can be associated with the expression of bcl-2 protein but that bcl-2-independent mechanisms also exist for such progression.
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PMID:Expression of bcl-2 and the progression of human and rodent prostatic cancers. 981 82

Extensive study of Bcl-2 protein expression in prostate cancer (CaP) tissues by means of immunocytochemistry (IC) has provided evidence that it positively correlates with high grade and stage of CaP and is associated with resistance to anti-androgen hormone therapy. In the present study, we investigated the expression of bcl-2 mRNA by non-isotopic in situ hybridization (ISH) in a series of 36 CaP with or without previous anti-androgen hormone treatment and performed a comparison with IC-detected Bcl-2 protein expression. Expression of Bcl-2 mRNA detected by ISH consistently differed from that detected by IC, especially in lymph node metastases (whereas no relevant variations of Bcl-2 mRNA levels were found in treated vs. untreated CaP patients). In particular, high content of Bcl-2 mRNA was found in 25/36 cases of CaP (in 13/18 hormone-treated and 12/18 untreated patients). Conversely, Bcl-2+ immunostaining was observed in only 7/36 CaP (in 4/18 hormone-treated and 3/18 untreated patients). Furthermore, ISH revealed Bcl-2 mRNA in 4/7 lymph node metastases, all 7 of which were Bcl-2(-) by IC. We conclude that, in the absence of a demonstrated post-transcriptional control of the bcl-2 gene, detection of mRNA by ISH in prostate archival tissues appears to be a reliable alternative method to assess differential expressions of the bcl-2 gene.
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PMID:Discrepancies between detection of Bcl-2 by in situ hybridization and immunocytochemistry in human prostate cancer tissues. 984 70

Androgen-independent growth of prostate cancer is correlated with expression of bcl-2. The impact of bcl-2 expression on the growth of prostate cancer cells following androgen ablation, was examined in the androgen-sensitive prostatic carcinoma cell line, LNCaP. Vector control and bcl-2 expressing LNCaP cells were grown subcutaneously in male nude mice. Tumor volume, apoptosis, and proliferation were assessed following castration. The levels of c-myc, p53, p21, bax, and bcl-2 protein were assessed by Western blotting. Bcl-2 expressing tumors exhibited a significant augmentation in growth compared to controls (p 0.01). No difference in the spontaneous rate of proliferation was observed between bcl-2 and control tumors, however, bcl-2 expressing tumors exhibited lower rates of apoptosis. Following orchiectomy the apoptotic index remained significantly lower in bcl-2 expressing tumors (p 0.002 at day 3). The proliferative index was maintained in bcl-2 expressing, but not control tumors following castration. This resulted in a significant growth advantage in bcl-2 tumors subsequent to androgen ablation (p 0.001). These changes were accompanied by alterations in the levels of gene products known to regulate the cell cycle and/or apoptosis. These results emphasize the significance of bcl-2 expression during prostate cancer progression and suggest possible mechanisms for the acquisition of androgen-independent tumor growth.
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PMID:Molecular correlates of bcl-2-enhanced growth following androgen-ablation in prostate carcinoma cells in vivo. 985 30

LNCaP tumors were treated by either administration of paclitaxel, thalidomide or by orchiectomy in order to determine their relationship with markers pertaining to the process of tumor growth, apoptosis or angiogenesis. Forty rats bearing LNCaP tumors were divided into 4 groups of 10 and treated by either paclitaxel (20 mg/kg x 5 days); thalidomide (200 mg/kg x 5 days/week x 5 weeks); or orchiectomy. After 6 weeks serum samples were removed for PSA determination and the animals sacrificed for evaluation of: A) tumor volume; B) tissue bcl-2, cyclin D, PSA and factor VIII immunohistochemically graded (0-5 scale) for marker expression; and C) serum PSA. Comparisons were made to untreated LNCaP tumors. Statistically significant differences were determined using the nonparametric Mann-Whitney test. Paclitaxel produced significant differences in volume (p < 0.001), expression of bcl-2 (p < 0.043), cyclin D (p < 0.023), tissue PSA (p < 0.001) and serum PSA (p < 0.019) levels. Thalidomide altered expression of bcl-2 (p < 0.011) and tissue PSA (p < 0.002). Orchiectomy altered volume (p < 0.002) and bcl-2 expression (p < 0.001). All three therapies have been suggested for prostate cancer and each produced alterations in accepted markers for treatment response (either reduced volume or serum PSA). Paclitaxel significantly influenced the most markers. Of interest was that all treatments, especially thalidomide, a known antiangiogenesis agent, reduced factor VIII, although not significantly. Evidently each treatment evokes different pathways of activity.
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PMID:Paclitaxel is more effective than thalidomide in inhibiting LNCaP tumor growth in a prostate cancer model. 1002 26

Metastatic prostate cancer is a leading cause of cancer-related death in men. Although most patients will respond to androgen ablation as initial systemic therapy, nearly all patients will develop androgen-independent prostate cancer (AI CaP) and will succumb to the disease. Advances in molecular biology have demonstrated mutations in and persistent expression of the human androgen receptor in metastatic disease. Furthermore, recent evidence indicates that an apoptotic block through p53 mutations or bcl-2 overexpression may have a potential role in the poor responses seen with standard chemotherapy. Presently, the six general treatment options available for AI CaP are best supportive care, radiation therapy, radioisotopes, secondline hormonal therapy, chemotherapy (single agent or combination), and investigational therapies such as monoclonal antibodies, cyclin-dependent kinase inhibitors, matrix metalloproteinase inhibitors, and antiangiogenesis agents, among others. None of these modalities have produced durable remissions, although some have demonstrated palliative benefit. The next generation of clinical trials should not consist of futile hormonal manipulations or repetitive chemotherapy. Therapeutic strategies aimed at circumventing molecular blocks to cell death or targeting unique cancer molecules and genes will be more likely to improve quality of life and longevity. Furthermore, the aggressive use of palliative care will ensure effective caring for patients and the healing of families in the absence of cure.
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PMID:Treatment options in androgen-independent prostate cancer. 1007 98


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