Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 tumor suppressor gene PTEN (MMAC1/TEP1) is lost frequently in advanced prostate cancer (PCa). However, the function of PTEN in tumorigenesis is not understood fully. In this study, we demonstrate that expression of Bcl-2 in prostate tumors correlates with loss of the PTEN protein. This finding was verified by studies in the PCa cell lines DU145, PC-3, LNCaP, and an androgen-refractory subline of LNCaP. Transient transfection of PTEN into the PTEN-null cells resulted in decreased levels of Bcl-2 mRNA and protein. These effects appear to be mediated at the level of gene transcription, since a Bcl-2 promoter-reporter construct was down-regulated by ectopic expression of PTEN in LNCaP cells. The inhibition of Bcl-2 required the lipid-phosphatase activity of PTEN and was blocked by overexpression of a constitutively active form of Akt. Moreover, the transcription-regulatory protein cAMP-response element-binding protein (CREB) may be involved, since decreased phosphorylation of CREB at Ser(133) was detected following PTEN expression, and ectopic expression of CREB repressed completely the PTEN-induced inhibition of Bcl-2 promoter activity. Furthermore, cotransfection of Bcl-2 and PTEN expression vectors rescued PTEN-induced cell death but not G(1) cell cycle arrest. Finally, forced expression of PTEN sensitized LNCaP cells to cell death induced by staurosporine, doxorubicin, and vincristine, and this chemosensitivity was attenuated by exogenous expression of Bcl-2. Taken together, these data demonstrate that loss of PTEN leads to up-regulation of the bcl-2 gene, thus contributing to survival and chemoresistance of PCa cells. These findings suggest that the PTEN gene and its regulated pathway are potential therapeutic targets in prostate cancer.
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PMID:PTEN induces chemosensitivity in PTEN-mutated prostate cancer cells by suppression of Bcl-2 expression. 1149 1

PC SPES (BotanicLab, Brea, California) an herbal supplement for patients with prostate cancer, is composed of 7 highly concentrated Chinese herbs and 1 US herb. It was developed in seeking positive attributes of Chinese and Western medicine for cancer treatment. Chemical standardization of this composition showed that baicalin is the most abundant active compound. Several reports on phase 2 clinical studies of PC SPES suggest that it is a well-tolerated active treatment for androgen-independent prostate cancer. In this report, data obtained from various laboratory experiments will be presented to elucidate the in vitro mechanism. Profound biologic effects of PC SPES on prostate cancer cells were observed on both androgen-dependent (LNCap) and androgen-independent (DU-145) cell lines. These effects include the following: (1) induction of cell apoptosis and cell cycle modulation; (2) inhibition of cell proliferation; (3) downregulation of bcl-2, bcl-6, proliferating cell nuclear antigen, and prostate-specific antigen proteins; (4) downregulation of androgen receptor (AR); and (5) upregulation of p53, bax, and p21 proteins. Concurrent animal studies using 2 different models, Copenhagen rats and nude mice, confirmed a dose-dependent suppressive effect of PC SPES on tumor volumes and tumor progression. Our results show that the cytotoxic and cytostatic properties of PC SPES are not entirely dependent on the presence of AR. The antitumor mechanism of PC SPES is complex. It involves multiple metabolic pathways, such that the whole extract acts on redundant mechanisms, which otherwise will permit cell survival if a single-target agent is used.
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PMID:In vitro mechanism of PC SPES. 1150 43

For the typical patient who has newly diagnosed prostate cancer, clinically organ-confined disease of moderate grade, and a PSA less than 10 ng/mL, the current role of imaging studies and molecular biomarkers is limited. Bone scans are not necessary for newly diagnosed men with a PSA less than 10 ng/mL in the absence of bone pain. Similarly, abdominal and pelvic CT scanning rarely provides any useful diagnostic or staging information when the PSA is less the 20 ng/mL and is indicated rarely. Endorectal coil MR imaging adds staging information for patients with a PSA between 10 and 20 ng/mL, a Gleason score of 7 or less, and 50% or more positive biopsies on a sextant sampling. Indium 111 capromab pendetide scanning (ProstaScint) is FDA-approved to evaluate newly diagnosed patients at high risk for metastases. These patients have a Gleason score of 7 or greater and a PSA greater than 20 ng/mL, a Gleason score of 8 to 10 regardless of the PSA value, or clinical stage T3 disease and a Gleason score of 6 or greater. RT-PCR testing of blood or bone marrow for prostate-specific or prostate cancer-specific gene expression, or "molecular staging," is a promising technique whose current use is still investigational. Much useful information may be gained by careful study of prostate needle biopsy material. Aside from current Gleason grading and the number or percentage of cores involved with cancer, no molecular biomarker is approved for clinical use. p27, p53, bcl-2, Ki-67 (MIB-1), and the assessment of neovascularity hold promise, but prospective multicenter studies are needed. In the long-term, multiple gene expression profiling of biopsy material using gene chips may revolutionize the care of patients with prostate cancer and those who elect radical prostatectomy.
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PMID:The role of imaging studies and molecular markers for selecting candidates for radical prostatectomy. 1159 Aug 6

Docetaxel, a semisynthetic taxane, has exhibited significant single-agent activity against prostatic tumors. In phase I/II studies, single-agent docetaxel and the combination of docetaxel plus estramustine were effective in inducing prostate-specific antigen reductions of > or =50% in men with androgen-independent prostate cancer (AIPC). The underlying reason for docetaxel's clinical activity against prostate cancer has been a focus of ongoing research. Docetaxel is believed to have a twofold mechanism of antineoplastic activity: (1) inhibition of microtubular depolymerization, and (2) attenuation of the effects of bcl-2 and bcl-xL gene expression. Taxane-induced microtubule stabilization arrests cells in the G(2)M phase of the cell cycle and induces bcl-2 phosphorylation, thereby promoting a cascade of events that ultimately leads to apoptotic cell death. In preclinical studies, docetaxel had a higher affinity for tubulin and was shown to be a more potent inducer of bcl-2 phosphorylation than paclitaxel. Laboratory evidence also supports the clinical evaluation of docetaxel-based combinations that include agents such as trastuzumab and/or estramustine. The pathways for docetaxel-induced apoptosis appear to differ in androgen-dependent and androgen-independent prostate cancer cells. Further elucidation of these differences will be instrumental in designing targeted regimens for the treatment of localized and advanced prostate cancer.
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PMID:Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. 1168 22

The transition from androgen-dependent to androgen-independent prostate cancer is accompanied by a number of molecular genetic changes, including overexpression of the bcl-2 gene. Overexpression of Bcl-2 protein decreases the pro-apoptotic response to such cellular insults as irradiation, chemotherapy, and androgen withdrawal. Reduction of Bcl-2 expression in hormone-refractory prostate cancer (HRPC) preclinical models markedly increases the antitumor efficacy of docetaxel both in vitro and in vivo. Thus, a phase I/II pharmacokinetic and biologic correlative study has been initiated in patients with HRPC to examine whether docetaxel therapy can be enhanced with a therapeutic antisense oligodeoxynucleotide (G3139) directed at bcl-2 gene expression. Semin Oncol 28 (suppl 15):67-70.
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PMID:Preliminary phase I results of G3139 (bcl-2 antisense oligonucleotide) therapy in combination with docetaxel in hormone-refractory prostate cancer. 1168 32

Cellular proliferation programmed cell death (apoptosis) are associated with tumor growth in general, and prostate cancer growth in particular. The aim of this study was to examine the expression of the apoptosis regulating genes bcl-2 and p53 and Gleason score in core needle biopsy specimens of prostate cancer using immunohistochemistry. We studied bcl-2 and p53 expression in 12 cases of low grade (Gleason score 2-5), 12 cases of intermediate grade (Gleason score 6-7) and 8 cases of high grade (Gleason score 8-10) prostate cancer. Overexpression of bcl-2 was noted in 3 of 32 patients (9.32%). One of them was high grade; others were intermediate grades. Expression of p53 was observed in 3 of low grades; others were high grade. The statistical analysis of present data suggest that there is no significant relation between p53 and bcl-2 expression and Gleason score in prostate cancer.
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PMID:Relationship between apoptosis regulator proteins (bcl-2 and p53) and Gleason score in prostate cancer. 1169 48

This work presents direct evidence that the bcl-2 gene is transcriptionally regulated by nuclear factor-kappa B (NF-kappa B) and directly links the TNF-alpha/NF-kappa B signaling pathway with Bcl-2 expression and its pro-survival response in human prostate carcinoma cells. DNase I footprinting, gel retardation and supershift analysis identified a NF-kappa B site in the bcl-2 p2 promoter. In the context of a minimal promoter, this bcl-2 p2 site 1 increased transcription 10-fold in the presence of the p50/p65 expression vectors, comparable to the increment observed with the consensus NF-kappa B site, while for the full p2 promoter region transcriptional activity was increased sixfold by over-expression of NF-kappa B, an effect eliminated by mutating the bcl-2 p2 site 1. The expression of Bcl-2 has been linked to the hormone-resistant phenotype of advanced prostate cancer. Here we show that an increase in the level of expression of Bcl-2 in the human prostate carcinoma cell line LNCaP observed in response to hormone withdrawal is further augmented by TNF-alpha treatment, and this effect is abated by inhibitors of NF-kappa B. Concomitantly, bcl-2 p2 promoter studies in LNCaP cells show a 40-fold increase in promoter activity after stimulation with TNF-alpha in the absence of hormone.
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PMID:Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. 1170 64

G-3139 is an antisense phosphorothioate oligodeoxynucleotide (AS PS ON) which suppresses bcl-2 expression and is being developed by Genta Inc for the potential treatment of various cancers [308375]. G-3139 is in various stages of phase I/lIa trials. One study, initiated in May 1999, at the Lombardi Cancer Center at Georgetown University Medical Center, US, will examine G-3139 in conjunction with docetaxel. In a phase I/IIa dose-escalating trial to treat non-Hodgkin's lymphoma (NHL), at the Royal Marsden NHS Trust, UK, no serious, clearly drug-attributable or doselimiting adverse effects were noted and in some patients encouraging signs of potential drug activity were observed. The responses included one patient in whom cancer mass was reduced and one who developed a complete response for over 38 weeks in duration [239159,291608,325262]. A new phase II protocol using G-3139 combined with standard chemotherapies in relapsed NHL patients has also begun [325262]. Other phase I/lIa studies include: the safety and efficacy of G-3139 in the treatment of hormone-resistant, metastatic prostate cancer, when administered with mitoxantrone [305822]; the treatment of relapsed follicular NHL, when administered with cyclophosphamide [311217]; the treatment of Stage III and IV metastatic malignant melanoma in combination with dacarbazine [289755]; the treatment of hormone-resistant, metastatic prostate cancer when administered over a significantly longer duration than studied previously and in combination with an androgen-receptor blocking agent [291608]. The National Cancer Institute (NCI) funded and conducted preclinical studies of G-3139 in July 1996 and in June 1998, the NCI and Genta entered into a Cooperative Research and Development Agreement (CRADA) for the development of G-3139 [290153]. Clinical trials,focusing on colorectal cancer, small cell lung cancer and leukemia, were underway as of April 1999. The company licensed the rights for the use of bcl-2 as a target for antisense and gene therapy-based treatments from the University of Pennnsylvania. In June 1998, Genta received two patents relating to its antisense compounds [289685].
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PMID:Technology evaluation: G-3139. 1171 6

Human metallothioneins (MTs) are low-molecular-weight, cysteine-rich, metal ion-binding proteins that constitute the majority of intracellular protein thiols. They are overexpressed in prostate and ovarian cancers and are believed to confer resistance to radiation and cytotoxic anticancer drugs. The aim of this study was to investigate the roles of MTs in prostate and ovarian cancer cells and their possible relationship with other cancer development and progression factors. The main problem in investigating the role of MT, however, is the absence of any known specific inhibitor. To this end, in a previous study, we had developed sequence-specific ribozymes (Rzs) targeting MT and had shown their in cellulo efficacy. Here we show that transient transfection of a vector carrying a hammerhead Rz (Rz4-9), designed to cleave class II MT, in the human prostate cancer cell line PC-3 and the ovarian cancer cell line SKOV-3 resulted in a dose-dependent attenuation of MT-II(a) transcripts and dramatic cell loss. Transient transfection with 2 microg of Rz4-9 vector DNA completely abolished MT-II(a) mRNA levels and induced a 94% and a 67% reduction in cell number in PC-3 cells and SKOV-3 cells, respectively. Fluorescence-activated cell sorting (FACS) showed that the Rz-induced cell loss probably was due to apoptosis, because it was associated with marked increases in the hypodiploid cell population, reaching maximums of 52% and 64% in cultures of PC-3 and SKOV-3, respectively. Additionally, annexin V-propidium iodide double-staining, followed by FACS, confirmed that Rz4-9-induced cell death was due to apoptosis and showed a vector DNA-dependent increase in late apoptotic cell numbers that reached maximums of 80% and 42%, respectively, in PC-3 and SKOV-3 cell cultures transfected with the highest concentration of vector DNA. In parallel experiments, transfection with a vector containing the enzymatically inactive mutant Rz-3-3 or the empty vector was not effective in inducing similar responses. The Rz-induced loss of MT-II(a) mRNA-associated cell death in these cancer cell lines was attended by dose-dependent downregulation of the proto-oncogene c-myc and the apoptosis inhibitory mediator bcl-2, suggesting that these signaling pathways are involved in the process. In conclusion, our data indicate that MT-II(a) is an important cell-survival or anti-apoptotic factor for prostate and ovarian cancer cells and that downregulation of its expression via transgene expression of a sequence-specific Rz is a feasible target for cancer therapy.
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PMID:Ribozyme-mediated downregulation of human metallothionein II(a) induces apoptosis in human prostate and ovarian cancer cell lines. 1180 57

Members of the bcl-2 gene family and endogenous inhibitors of cyclin-dependent kinases participate in the regulation of apoptosis and cell cycle in a diverse range of cell types and are implicated in the development of hormone refractory prostate cancer and resistance to anti-cancer therapy. The expression of several of these genes can be regulated by steroid hormones and related agents via their nuclear receptors. However, insufficient information considering the protein expression after the treatment by hormone antagonists is available. The aim of this study was to evaluate the expression of anti- and pro-apoptotic proteins, (Bcl-2, Bax), and to correlate this with the appearance of some nuclear receptors and cell cycle related proteins in androgen sensitive and androgen insensitive prostate cancer cell lines, LNCaP and DU-145, after the treatment by androgen antagonist bicalutamide. Our results revealed that androgen receptor (AR) expression in LNCaP cells decreased, however in DU-145 cells AR slightly increased following anti-androgen treatment. The same agent stimulated expression of p21Waf1/Cip5 and p27Kip1 in LNCaP, as well as in DU-145 cell lines. Bcl-2 level increased slightly in LNCaP cells and, in DU-145 cells was almost undetectable. Bax expression was not changed in LNCaP but significantly decreased in DU-145 cells. Similarly, retinoid X receptor beta (RXRbeta) level was significantly down regulated after 24 hours in DU-145 and also in LNCaP cells after 72 hours. These results confirm that androgen withdrawal therapy employing anti-androgens may elicit different signalling pathways in various types of prostate cancer that may be dependent on AR status and AR sensitivity.
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PMID:Androgen sensitivity related proteins in hormone-sensitive and hormone-insensitive prostate cancer cell lines treated by androgen antagonist bicalutamide. 1184 89


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