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Chronic azacitidine treatment results in differentiating effects, sensitizes against bicalutamide in androgen‐independent prostate cancer cells
Author(s) -
Gravina Giovanni Luca,
Festuccia Claudio,
Millimaggi Danilo,
Dolo Vincenza,
Tombolini Vincenzo,
de Vito Mariano,
Vicentini Carlo,
Bologna Mauro
Publication year - 2008
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20748
Subject(s) - bicalutamide , du145 , antiandrogen , prostate cancer , medicine , flutamide , cell growth , androgen , cancer research , endocrinology , androgen receptor , apoptosis , cancer , biology , lncap , hormone , genetics , biochemistry
BACKGROUND About 20–30% of hormone‐independent PCa are characterized by the extensive loss of AR expression that appears to occur at the transcriptional level. Treatment of AR‐negative PCa cells with demethylating agents (Aza‐CR) leads to expression of AR mRNA and protein. Here, we investigate the effect of Aza‐CR administered both acutely and chronically on AR expression, PSA expression, cell survival, and proliferation in androgen‐independent/AR‐negative PCa cells. We also studied whether epigenetically reactivated AR is a target for bicalutamide therapy. METHODS The in vitro effect of Aza‐CR as single agent and its ability to induce AR expression and to augment the efficacy to bicalutamide were assessed using two androgen‐independent and AR‐negative cell lines (PC3 and DU145). RESULTS Our results show that acute treatment (4 days) with Aza‐CR results in a relatively low decrease in cell proliferation with G2 cell cycle arrest and no significant evidence of apoptosis or AR expression. Interestingly, when Aza‐CR was chronically administered (20 days), this treatment resulted in marked decrease in tumor cell proliferation with significant increase in AR and PSA protein levels. Furthermore, following Aza‐CR chronic treatment the formerly androgen‐independent PC3 and DU145 cells increase their susceptibility to the apoptotic effects of bicalutamide. CONCLUSIONS Aza‐CR acute treatment has modest effects on androgen‐independent and AR‐negative PCa cell survival and proliferation, but chronic administration results in profound decrease in proliferation and in sensitization to antiandrogen agents. All these effects seem, in some measure, dependent on a partial restoration of androgen regulation. Prostate 68: 793–801, 2008. © 2008 Wiley‐Liss, Inc.