Suberoylanilide hydroxamic acid (vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation
Suberoylanilide hydroxamic acid (vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation
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DOI：
10.1158/1535-7163.mct-06-0144
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发表时间：
2007-01-01
影响因子：
5.7
通讯作者：
Butler, Lisa M.
中科院分区：
文献类型：
--
作者：
Marrocco, Deborah L.;Tilley, Wayne D.;Butler, Lisa M.
前列腺癌细胞的生长最初依赖于雄激素，雄激素消融治疗被用来控制肿瘤的生长。不幸的是，对雄激素消融治疗不可避免地发生抵抗，迫切需要更好的治疗晚期前列腺癌。组蛋白去乙酰化酶抑制剂，如亚eroylanilide羟肟酸（SAHA; vorinostat），是治疗包括前列腺癌在内的一系列恶性肿瘤的有希望的药物。SAHA在低微摩尔浓度下抑制雄激素反应性LNCaP前列腺癌细胞系的生长，并在较高浓度（>= 5 μ mol/L）下诱导caspase依赖性凋亡，与染色质凝聚、DNA断裂和线粒体膜去极化相关。基因谱分析和免疫印迹分析显示，与对照细胞相比，SAHA培养的LNCaP细胞中雄激素受体（AR） mRNA和蛋白水平降低，AR调节基因、前列腺特异性抗原水平相应降低。LNCaP细胞在无类固醇培养基中培养，细胞对SAHA显着增敏。此外，低剂量、次有效剂量的SAHA和AR拮抗剂比卡鲁胺联合使用可协同减少细胞增殖，增加caspase依赖性细胞死亡。外源性雄激素的加入阻止了细胞死亡的诱导，表明雄激素信号的抑制是协同作用所必需的。在亚有效浓度下，这些药物单独或联合使用对ar阴性PC-3前列腺癌细胞的增殖或死亡没有影响。我们的研究结果表明，SAHA可有效靶向AR信号轴，雄激素剥夺可使前列腺癌细胞对SAHA敏感。因此，针对AR通路不同组分的组合治疗可能提供更有效的策略来控制前列腺癌细胞的生长。
Growth of prostate cancer cells is initially dependent on androgens, and androgen ablation therapy is used to control tumor growth. Unfortunately, resistance to androgen ablation therapy inevitably occurs, and there is an urgent need for better treatments for advanced prostate cancer. Histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA; vorinostat), are promising agents for the treatment of a range of malignancies, including prostate cancer. SAHA inhibited growth of the androgen-responsive LNCaP prostate cancer cell line at low micromolar concentrations and induced caspase-dependent apoptosis associated with chromatin condensation, DNA fragmentation, and mitochondrial membrane depolarization at higher concentrations (>= 5 mu mol/L). Gene profiling and immunoblot analyses showed a decrease in androgen receptor (AR) mRNA and protein in LNCaP cells cultured with SAHA compared with control cells, with a corresponding decrease in levels of the AR-regulated gene, prostate-specific antigen. Culture of LNCaP cells in steroid-free medium markedly sensitized the cells to SAHA. Moreover, a combination of low, subeffective doses of SAHA and the AR antagonist bicalutamide resulted in a synergistic reduction in cell proliferation and increase in caspase-dependent cell death. Addition of exogenous androgen prevented the induction of cell death, indicating that suppression of androgen signaling was required for synergy. At the subeffective concentrations, these agents had no effect, alone or in combination, on proliferation or death of AR-negative PC-3 prostate cancer cells. Our findings indicate that SAHA is effective in targeting the AR signaling axis and that androgen deprivation sensitizes prostate cancer cells to SAHA. Consequently, combinatorial treatments that target different components of the AR pathway may afford a more effective strategy to control the growth of prostate cancer cells.