Differential Androgen Deprivation Therapies with Anti-androgens Casodex/Bicalutamide or MDV3100/Enzalutamide versus Anti-androgen Receptor ASC-J9® Lead to Promotion versus Suppression of Prostate Cancer Metastasis
Differential Androgen Deprivation Therapies with Anti-androgens Casodex/Bicalutamide or MDV3100/Enzalutamide versus Anti-androgen Receptor ASC-J9® Lead to Promotion versus Suppression of Prostate Cancer Metastasis
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DOI：
10.1074/jbc.m113.477216
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发表时间：
2013-07-05
影响因子：
4.8
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
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作者：
Lin, Tzu-Hua;Lee, Soo Ok;Chang, Chawnshang
尽管雄激素剥夺疗法（ADT）可以有效地减少前列腺癌（PCa）的大小，但其对PCa转移的影响尚不清楚。我们检查了接受ADT联合抗雄激素治疗的PCa患者的现有数据，以分析ADT对原发肿瘤大小、前列腺特异性抗原（PSA）值和转移发生率的影响。我们发现，目前ADT与抗雄激素可能导致原发性肿瘤缩小，PSA降低，但在一些PCa患者中转移增加。使用四种人PCa细胞系的体外和体内转移模型，我们评估了目前使用的抗雄激素药物Casodex/比卡鲁胺和MDV 3100/恩杂鲁胺，以及新开发的抗AR化合物ASC-J 9（R）和隐丹参酮对PCa细胞生长和侵袭的影响。体外结果显示，10 μ M Casodex或MDV 3100处理抑制PCa细胞生长，降低PSA水平，但显著增强PCa细胞侵袭。使用原位异种移植小鼠模型的体内小鼠研究也证实了这些结果。相比之下，ASC-J 9（R）在体外和体内模型中导致PCa细胞生长和细胞侵袭受到抑制。机制分析表明，这些Casodex/MDV 3100处理增强了TGF-β 1/Smad 3/MMP 9通路，但ASC-J 9（R）和隐丹参酮通过下调MMP 9表达显示出有希望的抗锡永作用。这些发现表明了使用抗雄激素的潜在风险，并提供了一种使用ASC-J 9（R）在去势抵抗阶段对抗PCa转移的潜在新疗法。
Despite the fact that androgen deprivation therapy (ADT) can effectively reduce prostate cancer (PCa) size, its effect on PCa metastasis remains unclear. We examined the existing data on PCa patients treated with ADT plus anti-androgens to analyze ADT effects on primary tumor size, prostate-specific antigen (PSA) values, and metastatic incidence. We found that the current ADT with anti-androgens might lead to primary tumor reduction, with PSA decreased yet metastases increased in some PCa patients. Using in vitro and in vivo metastasis models with four human PCa cell lines, we evaluated the effects of the currently used anti-androgens, Casodex/bicalutamide and MDV3100/enzalutamide, and the newly developed anti-AR compounds, ASC-J9 (R) and cryptotanshinone, on PCa cell growth and invasion. In vitro results showed that 10 mu M Casodex or MDV3100 treatments suppressed PCa cell growth and reduced PSA level yet significantly enhanced PCa cell invasion. In vivo mice studies using an orthotopic xenograft mouse model also confirmed these results. In contrast, ASC-J9 (R) led to suppressed PCa cell growth and cell invasion in in vitro and in vivo models. Mechanism dissection indicated these Casodex/MDV3100 treatments enhanced the TGF-beta 1/Smad3/MMP9 pathway, but ASC-J9 (R) and cryptotanshinone showed promising anti-inva-sion effects via down-regulation of MMP9 expression. These findings suggest the potential risks of using anti-androgens and provide a potential new therapy using ASC-J9 (R) to battle PCa metastasis at the castration-resistant stage.