Enzalutamide is a second-generation androgen receptor (AR) antagonist for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Unfortunately, AR dysfunction means that resistance to enzalutamide will eventually develop. Thus, novel agents are urgently needed to treat this devastating disease. Triptolide (TPL), a key active compound extracted from the Chinese herb Thunder God Vine (Tripterygium wilfordii Hook F.), possesses anti-cancer activity in human prostate cancer cells. However, the effects of TPL against CRPC cells and the underlying mechanism of any such effect are unknown. In this study, we found that TPL at low dose inhibits the transactivation activity of both full-length and truncated AR without changing their protein levels. Interestingly, TPL inhibits phosphorylation of AR and its CRPC-associated variant AR-V7 at Ser515 through XPB/CDK7. As a result, TPL suppresses the binding of AR to promoter regions in AR target genes along with reduced TFIIH and RNA Pol II recruitment. Moreover, TPL at low dose reduces the viability of prostate cancer cells expressing AR or AR-Vs. Low-dose TPL also shows a synergistic effect with enzalutamide to inhibit CRPC cell survival in vitro, and enhances the anti-cancer effect of enzalutamide on CRPC xenografts with minimal side effects. Taken together, our data demonstrate that TPL targets the transactivation activity of both full-length and truncated ARs. Our results also suggest that TPL is a potential drug for CRPC, and can be used in combination with enzalutamide to treat CRPC.

中文翻译：

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雷公藤甲素抑制AR信号通路抑制恩杂鲁胺抗性前列腺癌细胞的增殖。

Enzalutamide是第二代雄激素受体（AR）拮抗剂，用于治疗转移性去势抵抗性前列腺癌（mCRPC）。不幸的是，AR功能障碍意味着最终将对恩杂鲁胺产生抗药性。因此，迫切需要新型药物来治疗这种破坏性疾病。雷公藤甲素（TPL）是从中药雷神藤（雷公藤）中提取的关键活性化合物钩F.）在人前列腺癌细胞中具有抗癌活性。但是，TPL对CRPC细胞的作用以及任何这种作用的潜在机制尚不清楚。在这项研究中，我们发现低剂量的TPL可以抑制全长AR和截短AR的反式激活活性，而不会改变它们的蛋白质水平。有趣的是，TPL通过XPB / CDK7抑制Ser515上的AR及其与CRPC相关的变体AR-V7的磷酸化。结果，TPL抑制了AR与AR目标基因中启动子区域的结合，同时减少了TFIIH和RNA Pol II的募集。此外，低剂量的TPL降低了表达AR或AR-Vs的前列腺癌细胞的活力。低剂量TPL还显示与enzalutamide协同抑制体外CRPC细胞存活，并以最小的副作用增强恩杂鲁胺对CRPC异种移植物的抗癌作用。两者合计，我们的数据表明，TPL靶向全长和截短ARs的反式激活活性。我们的研究结果还表明，TPL是CRPC的潜在药物，可与enzalutamide联合用于治疗CRPC。