Division of Radiotherapy, Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
Prostate. 2010 Aug;70(11):1166-78. doi: 10.1002/pros.21151.
Epigenetic modifications play a key role in the in prostate cancer (Pca) progression to a hormone refractory state (HRPC) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. In this regard, 5-Azacitine (5-Aza) represents a promising epigenetic modulator. This study tested the hypothesis that 5-Aza may restore and enhance the responsiveness of HRPC cells to anti-hormonal therapy on Androgen receptor (AR) expressing (22rv1) and AR-deficient (PC3) cells.
The effects were studied in vitro and in vivo models. This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines.
This combined treatment up-regulated the expression of FasL, phospho-FADD, p16(INKA), Bax, Bak, and p21(WAF1), and inhibited FLIP, Bcl-2, and Bcl-XL expression. The re-activation of hormonal response of AR-negative PC3 cell line was partially due to the AR re-expression mediated by 5-Aza treatment. In contrast, the increase in the response to anti-androgenic therapy in 22rv1 did not correlate with AR expression levels. Furthermore, xenograft studies revealed that the combined treatment of 5-Aza with AR-antagonist Bicalutamide had additive/synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis.
So, this study strongly suggests a therapeutic potential of 5-Aza in combination with anti-androgen therapy in patients with in AR expressing and AR-deficient HRPC.
表观遗传修饰在前列腺癌（Pca）向激素抵抗状态（HRPC）的进展中起着关键作用，目前靶向表观遗传改变的药物的使用已成为癌症研究的一个热点。在这方面，5-氮杂胞苷（5-Aza）是一种很有前途的表观遗传调节剂。本研究检验了这样一个假设，即 5-Aza 可能恢复和增强 HRPC 细胞对表达雄激素受体（AR）的（22rv1）和 AR 缺失（PC3）细胞的抗激素治疗的反应。
在体外和体内模型中研究了这些影响。这种序贯治疗在 22rv1 和 PC3 肿瘤细胞系中诱导体外细胞周期停滞和细胞凋亡。
这种联合治疗上调了 FasL、磷酸化 FADD、p16(INKA)、Bax、Bak 和 p21(WAF1)的表达，并抑制了 FLIP、Bcl-2 和 Bcl-XL 的表达。AR 阴性 PC3 细胞系的激素反应重新激活部分是由于 5-Aza 治疗介导的 AR 重新表达。相比之下，22rv1 中对抗雄激素治疗反应的增加与 AR 表达水平无关。此外，异种移植研究表明，5-Aza 与 AR 拮抗剂比卡鲁胺联合治疗在体内抑制肿瘤生长具有相加/协同作用，而这些作用的潜在机制部分是通过诱导细胞凋亡介导的。
因此，本研究强烈提示 5-Aza 联合抗雄激素治疗在表达 AR 和 AR 缺失的 HRPC 患者中有治疗潜力。
