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)

A series of 20 patients with a histological diagnosis of prostatic cancer were treated with high doses of MAP (6alpha-methyl-17alpha-hydroxyprogesterone acetate). No response was noted in 9 patients with prostatic cancer in relapse. Objective and/or subjective response was noted in 6 of 11 patients who were untreated at the time of diagnosis.
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PMID:Progestogens in prostatic cancer. 65 69

On the basis of previous observations indicating that Medroxyprogesterone Acetate (MAP) administered in high doses induces leukocytosis and an increase in the platelet count, the Authors have studied the effect of high-dose MAP on leukocytes and platelets when it was combined with Chlorambucil (CLB) in patients suffering from ovarian cancer in various stages. 28 patients treated with high-dose MAP and CLB showed a statistically significant lower mean reduction of WBC count and reduction of the incidence, entity, and duration of the leukopenia as compared to 29 patients treated only with CLB. These effects were particularly evident when MAP was administered intramuscularly. It was not possible to evaluate the effect of high-dose MAP on the platelet count because the CLB regimen did not induce a significant decrease in it. These preliminary results are interesting because they suggest the possibility that high-dose MAP, which has already been utilized in oncology for its antitumor, analgesic, and anabolic activity in the treatment of breast, endometrial, renal, and prostatic cancer, might be able to be employed to reduce the myelotoxic effects of chemotherapy.
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PMID:[Effect of medroxyprogesterone acetate (MAP) in high doses on chlorambucil-induced bone marrow depression. Preliminary results]. 622 Jun 86

TNP-470, an analogue of fumagillin, has been shown to inhibit angiogenesis in vitro and in vivo. In 1992, TNP-470 entered clinical development for cancer as an anti-angiogenic agent. It is currently in Phase I/II trials in Kaposi's sarcoma, renal cell carcinoma, brain cancer, breast cancer, cervical cancer and prostate cancer. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose limiting toxicity (DLT). Terminal half-life values are short and have shown intermittent and intrapatient variation (range: 0.05 - 1.07 h). Recently, mechanistic studies have identified cell cycle mediators and the protein methionine aminopeptidase-2 (MetAP-2) as molecular targets of TNP-470 and fumagillin. Animal studies confirm some toxic effects on normal angiogenic processes such as the female reproductive system and wound healing, which will require caution and close monitoring in the clinic. TNP-470 is one of the first anti-angiogenic compounds to enter clinical trials, making it a valuable prototype for future trials of angiogenesis inhibitors in oncology.
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PMID:TNP-470: an angiogenesis inhibitor in clinical development for cancer. 1106 Jul 50

The early demonstrations that prostate cancer was hormone-sensitive initiated a therapeutic strategy of hormone ablation that is still in use today. Although chemical or surgical castration reduces androgen stimulation of the androgen receptor (AR) and produces tumor regression, little survival benefit is achieved. Patients with metastatic cancer eventually relapse as their tumors progress to hormone independence. The AR is a member of the steroid receptor family; however, it manifests many unique features including: N-terminal, C-terminal interactions and antiparallel dimerization, unique N-terminal domains for co-factor recruitment, AR-specific co-activators and upstream promoter/enhancer response elements that amplify AR-mediated responses. The AR is regulated by phosphorylation and cross-talk with several signaling pathways, including MAP kinases, PKA and PKC. Non-genomic effects of AR to regulate transcription factors elk-1 and -2 have also been demonstrated. These unique features suggest mechanisms by which novel therapeutics might target and influence AR-mediated actions. Progress in this direction has been realized with the recent synthesis of non-steroidal androgen agonists that may have tissue-selective effects.
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PMID:Prostate cancer and the androgen receptor: strategies for the development of novel therapeutics. 1112 64

Metastatic diseases of prostate cancer reveal high expression of alpha6 integrin and the activation of mitogen-activated protein kinases (MAP kinase). Therefore, the present study was conducted to examine whether MAP kinase pathway is involved in the alpha6 integrin gene expression in androgen-independent prostate cancer cell lines. alpha6 integrin mRNA expression, the alpha6 integrin promoter-induced luciferase activities and MAP kinase enzyme activities in androgen-independent LNCaP and PC-3 cell lines were higher than those in androgen-dependent LNCaP. Deletion and mutation analysis showed that Sp1 consensus sequence at -48 to -43 bp from the transcription start site was necessary for basal promoter activity. Binding of Sp1 to its consensus sequence in three cell lines was confirmed by electrophoretic mobility shift assays. Sp1 binding to its consensus sequence, as well as promoter activity and mRNA expression, were found to be inhibited by an inhibitor of MAP kinase kinase 1 and 2, U0126, in the androgen-independent cell lines. Our results indicate that the proximal Sp1 is necessary for basal promoter activity of the alpha6 integrin, suggesting that signal transduction from MAP kinases to activation of Sp1 might be involved in alpha6 integrin gene expression in androgen-independent prostate cancer cell lines.
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PMID:Mitogen-activated protein kinase pathway is involved in alpha6 integrin gene expression in androgen-independent prostate cancer cells: role of proximal Sp1 consensus sequence. 1133 92

Interleukin-6 (IL-6) induces prostate cancer (CaP) cell proliferation in vitro. Several lines of evidence suggest that IL-6 may promote CaP progression through induction of an androgen response. In this work, we explored whether IL-6 induces androgen responsiveness through modulation of androgen receptor (AR) expression. We found that in the absence of androgen, IL-6 increased prostate-specific antigen (PSA) mRNA levels and activated several androgen-responsive promoters, but not the non-androgen responsive promoters in LNCaP cells. Bicalutamide, an antiandrogen, abolished the IL-6 effect and IL-6 could not activate the PSA and murine mammary tumor virus reporters in AR-negative DU-145 and PC3 cells. These data indicate the IL-6 induces an androgen response in CaP cells through the AR. Pretreatment of LNCaP cells with SB202190, PD98059, or tyrphostin AG879 [p38 mitogen-activated protein kinase (MAPK), MAP/extracellular signal-regulated protein kinase kinase 1/2, and ErbB2 MAPK inhibitors, respectively) but not wortmannin (PI3-kinase inhibitor) blocked IL-6-mediated induction of the PSA promoter, which demonstrates that IL-6 activity is dependent on a MAPK pathway. Finally, IL-6 activated the AR gene promoter, resulting in increased AR mRNA and protein levels in LNCaP cells. These results demonstrate that IL-6 induces AR expression and are the first report of cytokine-mediated induction of the AR promoter. Taken together, our results suggest that IL-6 induces AR activity through both increasing AR gene expression and activating the AR in the absence of androgen in CaP cells. These results provide a mechanism through which IL-6 may contribute to the development of androgen-independent CaP.
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PMID:Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression. 1141 May 19

The insulin-like growth factor (IGF) axis is a complex system composed of 2 mitogenic ligands, IGF-I and -II, 2 receptors, IGF-1R and IGF-2R, and 6 binding proteins, IGFBP-1 to -6. The IGFBPs exert their actions through their regulation of IGF bioavailability for IGF receptors. In addition, some IGFBPs have also been found to have direct cellular actions independent of IGFs. IGFBP-2 is a major IGFBP in the prostate and in seminal fluid. IGFBP-2 levels, which are elevated in many malignancies, are markedly increased in prostate cancer, and show a positive correlation with prostate specific antigen (PSA) and prostate tumor aggressiveness. We investigated the potential role of IGFBP-2 in the pathogenesis of prostate cancer by evaluating its ability to stimulate growth and the expression and activity of the nuclear enzyme, telomerase. We found IGFBP-2 to have a modest suppressive effect on the growth of primary cultures of normal prostate epithelial cells and a potent IGF-antagonistic effect in these cells, similar to previous reports on the inhibitory nature of this molecule. Surprisingly, IGFBP-2 had a potent stimulatory effect on growth of LAPC-4 prostate cancer cells, an effect that was more pronounced in the absence of androgens. IGFBP-2 growth stimulation of LAPC-4 cells was completely blocked by MAP-kinase inhibitors and partially blocked by PI3-kinase inhibitors. IGFBP-2 stimulation of LAPC-4 cell growth seen in serum-free conditions was lost in the presence of 10% FBS. IGFBP-2 also had a growth stimulatory effect on DU 145 prostate cancer cells. IGFBP-2 significantly stimulated telomerase activity in LAPC-4 cells in the absence of androgens. In addition, IGFBP-2 significantly stimulated hTERT expression and telomerase activity in DU 145 cells. Thus, we demonstrated an inhibitory effect of IGFBP-2 on non-malignant prostate cells, but showed it to be stimulatory for prostate cancer cells in a MAP-kinase and androgen-modulated process. In conclusion, IGFBP-2 may play a role in the progression, but not in the initiation of the prostate cancer disease process, suggesting the existence of a molecular switch transitioning IGFBP-2 from a growth inhibitor to a pro-carcinogenic molecule.
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PMID:Novel stimulatory role for insulin-like growth factor binding protein-2 in prostate cancer cells. 1267 24

The proteome contains hundreds of proteins that in theory could be excellent therapeutic targets for the treatment of human diseases. However, many of these proteins are from functional classes that have never been validated as viable candidates for the development of small molecule inhibitors. Thus, to exploit fully the potential of the Human Genome Project to advance human medicine, there is a need to develop generic methods of inhibiting protein activity that do not rely on the target protein's function. We previously demonstrated that a normally stable protein, methionine aminopeptidase-2 or MetAP-2, could be artificially targeted to an Skp1-Cullin-F-box (SCF) ubiquitin ligase complex for ubiquitination and degradation through a chimeric bridging molecule or Protac (proteolysis targeting chimeric molecule). This Protac consisted of an SCF(beta-TRCP)-binding phosphopeptide derived from IkappaBalpha linked to ovalicin, which covalently binds MetAP-2. In this study, we employed this approach to target two different proteins, the estrogen (ER) and androgen (AR) receptors, which have been implicated in the progression of breast and prostate cancer, respectively. We show here that an estradiol-based Protac can enforce the ubiquitination and degradation of the alpha isoform of ER in vitro, and a dihydroxytestosterone-based Protac introduced into cells promotes the rapid disappearance of AR in a proteasome-dependent manner. Future improvements to this technology may yield a general approach to treat a number of human diseases, including cancer.
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PMID:Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation. 1452 58

The mechanisms that regulate prostate cancer growth and proliferation are not fully understood. IL-6, a multifunctional cytokine, has been shown to play an important role in prostate cancer biology. Functional role of MAP-kinase signal transduction pathways in prostate biology has not been evaluated in detail. In the present study we evaluated the effects of modulation of p42/44 MAP kinase signal transduction pathway on IL-6 expression and secretion by PC3 cells, a line of hormone refractory prostate cancer cells. Results presented, herein, demonstrate that modulation of p42/44 MAP kinase activity results in partial inhibition of synthesis and secretion of IL-6. These data suggest that modulation of p42/p44 may result in regulation of other survival pathways as well.
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PMID:p42/p44 Mitogen-activated protein kinase signal transduction pathway regulates interleukin-6 expression in PC3 cells, a line of hormone-refractory prostate cancer cells. 1565 4

The tumor suppressor gene p53 plays an essential role in cell proliferation and apoptosis. Due to its relevance to cancer therapy, most studies have focused on the cellular consequences of p53 activation in relation to cytotoxic drugs. 5-aza-2'-deoxycytidine (5-aza-CdR) is widely used as an anti-cancer drug for the treatment of leukemia and solid tumors. However, the mechanism by which 5-aza-CdR exerts its anti-neoplastic activity remains unclear. Here, we address the role of p53 in regulating cellular responses to 5-aza-CdR treatment in human prostate cancer cells. We found that 5-aza-CdR induces p53 and p21Waf1/Cip1 expression associated with inhibition of cell proliferation in LNCaP cells (p53 wild-type), but not in DU145 cells (p53 mutant). By using pifithrin-alpha, a chemical inhibitor of p53, we confirmed that the increase in p21Waf1/Cip1 expression and inhibition of cell proliferation in LNCaP cells by 5-aza-CdR is p53-dependent. Also, the activation of p53 and p21Waf1/Cip1 pathway by 5-aza-CdR modified multiple gene expressions including apoptotic target genes and MAP kinases in LNCaP cells. 5-aza-CdR-induced apoptosis in LNCaP cells is assessed by DNA fragmentation analysis. Furthermore, knockdown of p53 by pU6-p53 siRNA vector suggests the involvement of MAP kinases in the process of 5-aza-CdR-mediated activation of p53 pathway to inhibit cell proliferation and induce apoptosis. Finally, the comet or SCGE assay and methylation-sensitive restriction analysis demonstrated that 5-aza-CdR induced p53 and p21Waf1/Cip1 expression as a consequence of DNA damage and independent of DNA demethylation. Our findings suggest that 5-aza-CdR induces anti-neoplastic activity primarily through the activation of p53 pathway in response to DNA damage and subsequently leads to inhibition of cell proliferation as well as induction of apoptosis. Therefore, our data indicate that p53 status in tumor cells may be critical for the clinical efficacy and toxicity of 5-aza-CdR.
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PMID:Activation of p53/p21Waf1/Cip1 pathway by 5-aza-2'-deoxycytidine inhibits cell proliferation, induces pro-apoptotic genes and mitogen-activated protein kinases in human prostate cancer cells. 1575 79


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