Nevirapine restores androgen signaling in hormone-refractory human prostate carcinoma cells both in vitro and in vivo

Alessandra Cassano, Cinzia Bagala', Giovanni Schinzari, Michela Quirino, Sara Bianchetti, Gigliola Sica, Carlo Antonio Barone, Matteo Landriscina, Annamaria Piscazzi, Annarita Fabiano

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

BACKGROUND: Prostate carcinomas are androgen-dependent neoplasms which progress toward a hormone-independent phenotype during hormone-deprivation therapy. We evaluated nevirapine, a reverse transcriptase inhibitor, as a new treatment in hormone-refractory prostate carcinoma cells with the aim of restoring the androgen-dependency of tumor cells, the rationale being that endogenous reverse transcriptase is up-regulated in transformed cells and reverse transcriptase inhibitors exert a differentiating activity in human tumors. METHODS AND RESULTS: Nevirapine induced extensive reprogramming of gene expression in vitro with up-regulation of genes that might be silenced during prostate tumor progression (i.e., K18, PSA and androgen receptor) and down-regulation of genes involved in the progression toward an androgen-independent phenotype (i.e., K5, EGFR1, EGF and VEGF-A). Furthermore, nevirapine down-regulated the growth of prostate carcinoma xenografts in athymic mice and induced a differentiated phenotype in vivo with increased K18 expression. Interestingly, the drug restored androgen signaling by enhancing the ability of tumor cells to respond to dihydrotestosterone stimulation and to the antiproliferative activity of the androgen receptor blocker bicalutamide. Finally, nevirapine pretreatment increased the susceptibility of tumor cells to docetaxel, by enhancing their ability to undergo apoptosis. CONCLUSIONS: These data suggest that nevirapine may be clinically tested in human hormone-refractory prostate carcinoma to restore the susceptibility to androgen deprivation therapy or to docetaxel. 2009 Wiley-Liss, Inc.
Original languageEnglish
Pages (from-to)744-754
Number of pages11
JournalProstate
Volume69
Publication statusPublished - 2009

Keywords

  • androgen deprivation therapy
  • docetaxel
  • endogenous reverse transcriptase
  • hormone-refractory prostate carcinoma
  • nevirapine

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