Chronic azacitidine treatment results in differentiating effects, sensitizes against bicalutamide in androgen-independent prostate cancer cells.
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.
Gravina
Giovanni Luca
GL
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy. giovanniluca.gravina@poste.it
Festuccia
Claudio
C
Millimaggi
Danilo
D
Dolo
Vincenza
V
Tombolini
Vincenzo
V
de Vito
Mariano
M
Vicentini
Carlo
C
Bologna
Mauro
M
D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology*
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; C411744:DMAP1 protein, human; D009570:Nitriles; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D012097:Repressor Proteins; D014105:Tosyl Compounds; C053541:bicalutamide; D017430:Prostate-Specific Antigen; D001374:Azacitidine