Gravina Giovanni Luca, Festuccia Claudio, Millimaggi Danilo, Dolo Vincenza, Tombolini Vincenzo, de Vito Mariano, Vicentini Carlo, Bologna Mauro
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
Prostate. 2008 May 15;68(7):793-801. doi: 10.1002/pros.20748.
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.
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).
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.
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.
约20%-30%的激素非依赖性前列腺癌的特征是雄激素受体（AR）表达广泛缺失，这似乎发生在转录水平。用去甲基化剂（Aza-CR）处理AR阴性前列腺癌细胞可导致AR mRNA和蛋白表达。在此，我们研究急性和慢性给予Aza-CR对激素非依赖性/AR阴性前列腺癌细胞中AR表达、前列腺特异性抗原（PSA）表达、细胞存活和增殖的影响。我们还研究了表观遗传重新激活的AR是否是比卡鲁胺治疗的靶点。
使用两种激素非依赖性和AR阴性细胞系（PC3和DU145）评估Aza-CR作为单一药物的体外作用及其诱导AR表达和增强比卡鲁胺疗效的能力。
我们的结果表明，Aza-CR急性处理（4天）导致细胞增殖相对轻度下降，伴有G2期细胞周期停滞，且无明显凋亡或AR表达证据。有趣的是，当长期给予Aza-CR（20天）时，这种处理导致肿瘤细胞增殖显著下降，AR和PSA蛋白水平显著增加。此外，Aza-CR长期处理后，先前激素非依赖性的PC3和DU145细胞对比卡鲁胺的凋亡作用敏感性增加。
Aza-CR急性处理对激素非依赖性和AR阴性前列腺癌细胞存活和增殖有适度影响，但长期给药导致增殖显著下降并对抗雄激素药物敏感。所有这些作用在某种程度上似乎依赖于雄激素调节的部分恢复。
