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)

Previous studies (Y. Guo and N. Kyprianou, Cell Growth Diff., 9: 185-193, 1998) have demonstrated that overexpression of transforming growth factor (TGF) beta type II receptor (TbetaRII) gene in human prostate cancer cells LNCaP, which are refractory to TGF-beta1 and lack TbetaRII receptor expression, can restore TGF-beta1 sensitivity and suppress in vitro tumorigenic growth by inhibiting cell proliferation. In the present study, we investigated the effect of TbetaRII receptor overexpression in LNCaP cells on apoptosis induction and tumorigenicity. The ability of LNCaP cells that overexpress TbetaRII to undergo apoptosis in response to TGF-beta1 was examined by DNA fragmentation and terminal transferase-mediated dUTP-biotin end labeling analysis. To explore the potential apoptotic nature of TGF-beta1-mediated antitumor effect against human prostate cancer cells, the expression of apoptotic proteins bcl-2 and bax was examined by Western blot analyses. The significance of caspase 1 in TGF-beta1-mediated apoptosis was also determined by examining the expression and activation of caspase 1 by reverse transcription-PCR and Western blot analyses, respectively. Comparative analysis of tumorigenicity of the parental LNCaP and TbetaRII-overexpressing clones in severely combined immunodeficient mice revealed a significant suppression of tumor growth in TbetaRII transfectant clones compared with parental LNCaP cells and neomycin-control clones (P < 0.05). A significantly higher incidence of endogenous apoptosis was observed in TbetaRII clone-61-derived tumor compared with the parental LNCaP tumors. This induction of apoptosis in the LNCaP tumors with restored TGF-beta1 signaling was associated with decreased bcl-2 expression, increased bax, and caspase-1 immunoreactivty. Moreover, an increased expression of the cyclin-dependent kinase inhibitor p27Kip1 was detected in TbetaRII-overexpressing tumors compared with the parental tumors. LNCaP TbetaRII transfectant cells exhibited a marked induction of apoptosis, paralleled with a decreased bcl-2 expression in response to TGF-beta1 treatment in vitro. This TGF-beta1-mediated apoptosis induction in TbetaRII transfectant cells was significantly protected by the caspase-1 inhibitor (zVAD-fmk) in a dose-dependent manner. Furthermore, a significant temporal induction of caspase-1 mRNA and protein expression was detected in TbetaRII cells in response to TGF-beta1 treatment. Our findings suggest that restoration of TGF-beta1 signaling suppresses tumorigenicity of human prostate cancer cells by inducing apoptosis, potentially via a caspase-1-mediated pathway.
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PMID:Restoration of transforming growth factor beta signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of caspase-1-mediated apoptosis. 1009 72

Most prostate cancers eventually develop resistance to hormonal therapy and chemotherapies. Many mechanisms for resistance to chemotherapy have been identified. Mutations or inactivation of the p53 suppressor gene and overexpression of bcl-2 are among such mechanisms. Mutations in the p53 gene can lead to resistance to certain chemotherapy agents, and such mutations are seen more often in metastatic than in primary prostate cancers. Thus, agents that are active in the setting of mutated p53 may have some advantage in prostate cancer. Overexpression of bcl-2 occurs frequently in prostate cancer and is associated with both hormonal therapy and chemotherapy resistance. In experimental systems, bcl-2 overexpression occurs after androgen deprivation and transfection of bcl-2 into sensitive cell lines makes them resistant to chemotherapy and hormonal therapies. Bcl-2 can be inactivated by phosphorylation as occurs with taxanes. The retinoids, as a class, can inhibit the growth of resistant cell lines that overexpress bcl-2, and the combination of interferon (IFN) and cis-retinoic acid (CRA) demonstrated increased antitumor activity. In our cell line model the combination of IFN and CRA greatly enhanced the cytotoxicity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). Based on these observations, we conducted a phase I/II trial of CRA and IFN-alpha in patients with biochemical recurrence of prostate cancer. Twenty-six percent achieved a decrease of prostate-specific antigen (PSA), which was correlated to elevated serum transforming growth factor-beta. We then conducted a phase I trial of 13-CRA, IFN-alpha, and escalating doses of paclitaxel. Eighteen patients were treated with 1 mg/kg CRA and 1x10(6) unit IFN on days 1 to 4 and paclitaxel at doses from 100 to 175 mg/m2. Eleven patients received the 175 mg/m2 paclitaxel dose. Two patients in the phase I study achieved partial responses (one cervix and one prostate cancer). We subsequently initiated a phase II study of 13-CRA, IFN-alpha, and paclitaxel in hormone refractory prostate cancer. For entry patients must show progressive disease after androgen ablation. To test the mechanism of action, we are assaying peripheral blood monocytes and, when possible, tumor tissue for bcl-2 expression. As our understanding of the mechanisms of tumor resistance to chemotherapy improves, we will be able to design better approaches in treatment targeted to overcome the mechanisms of resistance.
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PMID:Overcoming bcl-2- and p53-mediated resistance in prostate cancer. 1019 Jul 92

To explore the mechanisms underlying the chemopreventive effects of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) in prostate cancer, we evaluated the anti-proliferative and apoptosis-inducing effects of 4-HPR in the androgen-sensitive human prostate cancer cell line LNCaP. 4-HPR decreased the number of viable LNCaP cells (as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay) in a dose-dependent manner. Although 4-HPR exerted a modest G1 cell-cycle block (as determined by flow cytometry), its effect on reduced cell number appeared to result primarily from induction of apoptosis (as measured by an enzyme-linked immunosorbent assay and flow-cytometric assays). The mitogenic effects of R1881, a non-metabolizable androgen that potently induces LNCaP cell proliferation, was completely blocked by greater than 0.5 microM 4-HPR. Furthermore, increasing the R1881 concentration in the presence of 2.0 microM 4-HPR increased apoptotic cell death. 4-HPR decreased prostate-specific antigen (PSA) protein levels in conditioned medium and decreased PSA mRNA expression. 4-HPR also decreased the ratio of bcl-2 to bax mRNA expression in LNCaP cells by approximately 45%, indicating that the apoptotic effects of 4-HPR may be mediated, at least in part, by alterations in the bcl-2/bax-regulated apoptotic pathway. N-acetylcysteine (4 mM) completely blocked the anti-proliferative and apoptotic-inducing effects of 4-HPR, suggesting that an oxidative mechanism may be involved. We concluded that (i) 4-HPR exerts growth-suppressive and apoptotic effects on LNCaP cells, (ii) 4-HPR can interact with androgen to suppress proliferation and induce apoptosis, (iii) the apoptotic effects of 4-HPR may be mediated in part by the bcl-2/bax pathway, and (iv) a pro-oxidant mechanism may contribute to the anti-proliferative and apoptotic-inducing effects of 4-HPR.
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PMID:Mechanistic studies of the effects of the retinoid N-(4-hydroxyphenyl)retinamide on prostate cancer cell growth and apoptosis. 1020

Within the past 5 years, research has increasingly addressed molecular alterations in prostate cancer (CaP). Mutations of tumor suppressor gene p53 have been found in a variety of cancers, including urologic neoplasms. Several studies have been conducted on CaP specimens, citing frequencies of p53 alterations in localized cancers ranging from 4 to 60% and with more advanced hormone refractory disease, as high as 94%. The majority of studies have revealed a low percentage of p53 abnormalities in early-stage (clinically organ-confined) CaP. The overwhelming bulk of evidence suggests that the frequency of p53 abnormalities does increase with disease progression and is highest in tissues from patients with hormone-refractory prostate cancer. More recently, our group and others have found that focal p53 expression in the primary tumor by immunohistochemistry is predictive of cancer recurrence after radical prostatectomy. bcl-2 is an oncogene critically involved in the apoptosis, or programmed cell death. Overexpression of bcl-2 protein by immunohistochemistry has been commonly detected in advanced hormone refractory CaP. Our group recently has also shown that bcl-2 protein expression in primary CaP is a predictor of cancer recurrence after radical prostatectomy. Furthermore, the combination of p53 and bcl-2 protein expression were both independent predictors of recurrence after surgery. Most recently, we have shown that even though p53 and bcl-2 are predictive biomarkers when sampling the radical prostatectomy specimen, they are not useful to predict postoperative recurrence when sampling the pretreatment needle biopsy. Ki-67 is an antigen of cellular proliferation. Immunohistochemical staining for Ki-67 in archival material can be performed using the MIB-1 antibody. Unlike our results with p53 and bcl-2, Ki-67 protein expression by immunohistochemistry using MIB-1 was not an independent prognostic marker for cancer recurrence after radical prostatectomy although it may have clinical utility in subsets of patients. Assessment of MIB-1 staining in CaP needle biopsy samples is underway. Tumor neovascularity, or angiogenesis, is necessary for cancers to grow and metastasize. Angiogenesis in CaP as a prognostic marker has received recent attention. Most studies have used factor VIII immunohistochemical staining and increased angiogenesis has been suggested as a staging and prognostic marker. Our group has recently conducted a large study of radical prostatectomy patients and used CD34 antigen immunohistochemistry to assess neovascularity. We did not find that this biomarker assessment was an independent prognostic marker of cancer recurrence after radical prostatectomy. Further work is being conducted in needle biopsy samples. More research is needed to assess new biomarkers and, most importantly, to standardize the methodology for sampling and assaying biomarkers in heterogeneous and multifocal prostate cancer.
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PMID:Angiogenesis, p53, bcl-2 and Ki-67 in the progression of prostate cancer after radical prostatectomy. 1032 96

Based on autopsy and epidemiologic data the lifetime risk of developing prostate cancer for a 50-year-old man is 42%, but only 9.5% will develop a clinically manifest disease and only 2.9% will die from this disease. The actual rate of carcinoma detection using PSA, digital rectal examination and transrectal ultrasound is 1%-3%. The majority of prostate carcinoma never progress to clinically significant disease, a minor portion remains confined to the prostate for many years and other carcinomas progress rapidly to a life threatening disease. The dilemma for clinicians and pathologists dealing with this tumor is how to distinguish these three biologically different types. Pathologists play an important role in preoperative diagnosis and in the postoperative prognosis oriented evaluation of the prostatectomy material. Volunteer PSA screening trials have led to an enormous increase in core-needle biopsies of the prostate. Since biopsies are often performed in men without palpable or ultrasound-visible nodules, are now faced with an increasing number of equivocal morphological features which can not be clearly defined, even with standardized criteria. Further investigations are also required to elucidate the clinical importance of PIN detection in biopsies. The heterogeneous histomorphology of prostate carcinoma can not be used as a prognostic factor. Therefore the histological grading is a very important factor for the assessment of prognosis. Carcinoma grading in biopsies is also of limited value in predicting tumor stage. Currently, several different grading systems are in use. Gleason's grading is the most favored, although its reproducibility is very low. The stage of the prostate carcinoma is still the best prognostic factor. In order to accurately assess the pTNM stage, TUR or prostatectomy material must be subject to extensive and standardized processing. Additionally, the volume of the tumor, the vascular invasion, the amount of extension of the tumor through the prostate capsule and perhaps the neoangiogenesis might be valid prognostic factors for disease progress and for survival. The value of novel methods (p53, bcl-2, apoptosis, microvessel density, interphase cytogenetics, androgen receptor mutation, neuroendocrine cells, E-Cadherin) remains to be proved. DNA ploidy is a good prognostic factor after prostatectomy and can be used to plan adjuvant hormone therapy.
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PMID:Pathology of prostate cancer. Old problems and new facts. 1035 66

The molecular mechanisms leading to androgen-independent growth in prostate cancer (PC) are poorly understood. Androgen deprivation therapy (ADT) results physiologically in a decrease in proliferation and an increase in programmed cell death (PCD)/apoptosis. The aim of our study was to get more insight into these processes in prostatic carcinomas before and after ADT. For this purpose, immunohistologic staining for the androgen receptor (AR) molecule, the Ki-67 antigen, the bcl-2 oncoprotein, the p53 protein and its physiologic effector, p21/WAF1, was performed on archival material. PCD was visualized by enzymatic detection of DNA fragmentation. Specimens from 69 PC patients after ADT were studied in correlation to histopathology and prognosis. In 42 cases, corresponding tumour tissue from the untreated primary tumours could be analysed comparatively. Before ADT, histologic grade was associated with Ki-67 index (P < 0.0001, Spearman correlation) and PCD rate (P < 0.05, Spearman correlation). Ki-67 index correlated with PCD rate (P < 0.05, Spearman correlation) and p21/WAF1 expression (P < 0.01, Fisher's exact test). p21/WAF1 expression was the only statistically significant prognostic factor for shorter survival (P < 0.002, log-rank test). All p21/WAF1-positive cases showed high Ki-67 index and high histologic grade. After ADT, loss of AR expression was associated with high Ki-67 index, whereas histologic signs of regression correlated negatively with Ki-67 index (P < 0.001, Pearson chi2 test). p21/WAF1 expression increased significantly (P < 0.02, McNemar test) and correlated with p53 accumulation (P < 0.0001, Pearson chi2 test). Most significant prognostic parameter after conventional ADT was high-rate p21/WAF1 expression (> 50% of tumour cells; P < 0.00001, log-rank test). This study demonstrates that p21/WAF1 overexpression before and after ADT characterizes a subgroup of advanced PC with paradoxically high proliferation rate and significantly worse clinical outcome. This finding might be clinically useful for planning therapy in these patients.
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PMID:Proliferation- and apoptosis-associated factors in advanced prostatic carcinomas before and after androgen deprivation therapy: prognostic significance of p21/WAF1/CIP1 expression. 1040 65

Over-expression of bcl-2, a potent anti-apoptosis protein, is likely to be one of the genetic mechanisms through which human prostate cancer cells develop resistance to hormonal and other forms of therapy. To develop a therapeutic agent for hormone-resistant prostate cancer based on suppression of bcl-2 expression, we had previously designed and synthesized a dual-hammerhead ribozyme capable of recognizing and specifically cleaving human bcl-2 mRNA in vitro as well as in vivo. To increase the efficiency by which the anti-bcl-2 ribozyme can be delivered to target cells, we have created a recombinant replication-deficient (defective) adenoviral agent capable of expressing the anti-bcl-2 ribozyme upon infection. This viral agent effectively reduces intracellular levels of bcl-2 mRNA and protein in cultured LNCaP prostate cancer cells following standard infection procedures. Likewise, the defective adenovirus-anti-bcl-2 ribozyme induces extensive apoptosis in several androgen-sensitive (LNCaP) and androgen-insensitive (LNCaP/bcl-2 and PC-3) human prostate cancer cell lines that express differing amounts of bcl-2 protein. One androgen-insensitive prostate cancer cell line, DU-145, lacking in bcl-2 expression, was found to be completely refractory to the effects of the virus ribozyme, supporting the concept that the cytotoxic effects of the ribozyme are based solely on its effects on bcl-2 expression. Our results support further development of this adenovirus/anti-bcl-2 ribozyme for potential gene therapeutic purposes in certain forms of hormone-resistant prostate cancer where over-expression of bcl-2 proto-oncogene is indicated.
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PMID:A recombinant defective adenoviral agent expressing anti-bcl-2 ribozyme promotes apoptosis of bcl-2-expressing human prostate cancer cells. 1044 52

We examined the activity of two metabolites of sulindac (a nonsteroidal anti-inflammatory drug), sulindac sulfide and sulindac sulfone (exisulind, Prevatec), and a novel highly potent analog of exisulind (CP248) on a series of human prostate epithelial cell lines. Marked growth inhibition was seen with the BPH-1, LNCaP, and PC3 cell lines with IC50 values of about 66 microM, 137 microM, and 64 nM for sulindac sulfide, exisulind, and CP248, respectively. DNA flow cytometry and 4',6'-diamido-2-phenylindole (DAPI) staining indicated that these three compounds also induced apoptosis in all of these cell lines. Similar growth inhibition also was seen with the PrEC normal human prostate epithelial cell line, but these cells were resistant to induction of apoptosis at concentrations up to 300 microM, 1 mM, and 750 nM of sulindac sulfide, exisulind, and CP248, respectively. Derivatives of LNCaP cells that stably overexpress bcl-2 remained sensitive to growth inhibition and induction of apoptosis by these compounds. In vitro enzyme assays indicated that despite its high potency in inhibiting growth and inducing apoptosis, CP248, like exisulind, lacked cyclooxygenase (COX-1 and COX-2) inhibitory activity even at concentrations up to 10 mM. Moreover, despite variations of COX-1 and COX-2 expression, the three benign and malignant prostate cell lines showed similar sensitivity to growth inhibition and induction of apoptosis by these three compounds. Therefore, sulindac derivatives can cause growth inhibition and induce apoptosis in human prostate cancer cells by a COX-1 and -2 independent mechanism, and this occurs irrespective of androgen sensitivity or increased expression of bcl-2. These compounds may be useful in the prevention and treatment of human prostate cancer.
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PMID:Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines. 1048 67

Estramustine phosphate has been used frequently alone or in combination with other drugs for the treatment of hormone-refractory prostate cancer. Estramustine is one of the major active metabolites of estramustine phosphate in vivo. We recently demonstrated that estramustine acts as an androgen antagonist, and the combination of estramustine with [3'-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) results in synergistic cytotoxicity. Unlike other regulators of microtubules, such as paclitaxel, the present study demonstrated that estramustine alone or in combination with PSC 833 did not induce bcl-2 phosphorylation in LNCaP cells. No synergism between estramustine and PSC 833 in the induction of bcl-2 phosphorylation was obtained in MCF-7 cells exposed for 16 hr to estramustine (5-15 microM) and PSC 833 (5 microM). A significant synergistic antiandrogenic effect as measured by the inhibition of dihydrotestosterone-induced reporter gene luciferase expression in both wild-type and mutated androgen receptor (AR) cDNA-transfected HeLa cells was observed when the cells were exposed to estramustine and PSC 833. Treatment of LNCaP cells with estramustine alone (5-15 microM) resulted in a decrease of AR expression and phosphorylation. This effect was enhanced markedly by PSC 833. A strong correlation between AR phosphorylation and expression of the AR target gene PSA was obtained in dihydrotestosterone-stimulated LNCaP cells. The up-regulated PSA expression is a function of the level of the phosphorylated AR (r = 0.9814), but not the dephosphorylated form of the receptor protein (r = 0.4808). Thus, our studies suggest that the synergism between estramustine and PSC 833 in LNCaP cells is a consequence of inhibition of AR expression and phosphorylation, thus leading to interruption of AR-mediated gene expression.
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PMID:Synergistic effect of estramustine and [3'-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) on the inhibition of androgen receptor phosphorylation in LNCaP cells. 1048 69

The goal of this study is to investigate the molecular mechanisms of androgen-independent growth in prostate cancer. We have established an androgen-independent prostatic carcinoma LNCaP-AI (defined as a LNCaP cell line that is capable of growing in charcoal-stripped serum) from the androgen-dependent LNCaP-FGC cells. In contrast to the androgen-independent PC-3 human prostate cancer cells, LNCaP-AI cells still express a similar level of androgen receptor as their parental cells and are sensitive to androgen stimulation. Compared with the parental LNCaP-FGC cells, LNCaP-AI cells are more resistant to apoptosis induced by 12-O-tetradecanoylphorbol-13-acetate and express a much higher level of antiapoptotic gene bcl-2 and cyclin-dependent kinase inhibitor p21, which may confer an enhanced antiapoptosis phenotype. On the other hand, expression of cyclin-dependent kinase inhibitor p16 is significantly reduced in the LNCaP-AI cells, implying the release of an inhibitory effect of p16 on cell cycle progression. Taken together, our results suggest that multiple factors contribute to the development of androgen-independent growth of prostatic carcinoma cells, including enhancement of cell antiapoptosis function, release of cell cycle inhibition, and stimulation of cell proliferation by alternative signaling pathways.
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PMID:Molecular mechanisms of androgen-independent growth of human prostate cancer LNCaP-AI cells. 1053 31


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