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  • Title: Chemosensitization of androgen-independent prostate cancer with neutral endopeptidase.
    Author: Sumitomo M, Asano T, Asakuma J, Asano T, Nanus DM, Hayakawa M.
    Journal: Clin Cancer Res; 2004 Jan 01; 10(1 Pt 1):260-6. PubMed ID: 14734478.
    Abstract:
    PURPOSE: We investigated whether neutral endopeptidase (NEP) could augment chemosensitivity to anticancer drugs by promoting protein kinase C (PKC)delta-mediated mitochondrial apoptosis in prostate cancer (PC) cells. EXPERIMENTAL DESIGN: Human PC cell lines LNCaP and PC-3, and a normal prostate epithelial cell line (PrEC) were used. The protein expression was detected by Western blot analysis, and the protein turnover was determined by pulse-chase assay. Apoptotic ratio was measured by annexin V staining. RESULTS: Western blot analyses and pulse-chase assays showed that the specific NEP inhibitor CGS24592 decreased PKCdelta protein expression by promoting PKCdelta protein degradation in NEP-expressing LNCaP cells. Conversely, recombinant NEP (rNEP) increased PKCdelta protein expression by delaying PKCdelta protein degradation in NEP-negative PC-3 cells. Apoptosis assays showed that rNEP promoted anticancer drug-induced apoptosis in PC-3 cells specifically through PKCdelta activity that mediated anticancer drug-induced mitochondrial change such as cytochrome-c release and caspase-9 activation. Of note, rNEP was able to increase PKCdelta protein expression predominantly in PC-3 cells rather than in PrEC cells. Treatment with rNEP before subtoxic concentrations of etoposide (0.1 micro M) significantly promoted mitochondrial apoptosis compared with only etoposide in PC-3 cells (P < 0.01) but not in PrEC cells. CONCLUSIONS: These results suggest that NEP enzyme activity contributes to anticancer drug-induced PC cell apoptosis dependent on PKCdelta-mediated mitochondrial events. More importantly, the combination of NEP with anticancer drugs may be a promising therapeutic modality because rNEP is able to augment chemosensitivity in androgen-independent PC with minimal toxicity in normal tissues.
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