Triptolide Inhibits the AR Signaling Pathway to Suppress the Proliferation of Enzalutamide Resistant Prostate Cancer Cells.
雷公藤内酯醇抑制 AR 信号通路抑制 Enzalutamide 抗性前列腺癌细胞的增殖。
Phosphorylation. Triptolide, Enzalutamide, Castration-resistant prostate cancer, Androgen receptor
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摘要

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.

译文

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 功能障碍意味着对 enzalutamide 的耐药性最终会发展。因此,迫切需要新的药物来治疗这种毁灭性的疾病。雷公藤甲素 (TPL) 是从中草药雷公藤中提取的一种关键活性化合物,对人前列腺癌细胞具有抗癌活性。然而,TPL 对 CRPC 细胞的作用以及任何此类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 抑制全长和截短的 AR 的反式激活活性,而不改变它们的蛋白质水平。有趣的是,TPL 通过 XPB/cdk7 抑制 AR 及其 CRPC 相关变体 AR-V7 在 Ser515 的磷酸化。因此,TPL 抑制 AR 靶基因中 AR 与启动子区域的结合,同时减少 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 还显示出与 enzalutamide 在体外抑制 CRPC 细胞存活的协同作用,并增强 enzalutamide 对 CRPC 移植瘤的抗癌作用,副作用最小。综上所述,我们的数据表明 TPL 靶向全长和截短的 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 联合使用治疗 CRPC。

Triptolide

重症 雷公藤甲素 药物
概述  :  

雷公藤甲素(triptolide,TP),又称雷公藤内酯、雷公藤内酯醇,是从雷公藤中分离出的环氧化二萜内酯化合物,也是中药雷公藤的主要活性成分之一。雷公藤甲素分子式为C20H24O6,相对分子质量为360。 目前雷公藤提取物制剂“雷公藤多甙片”已成功上市,其包含雷公藤甲素等多种雷公藤活性成分,可祛风解毒、除湿消肿、舒筋通络等,常被用于治疗类风湿性关节炎、肾病综合征、自身免疫性肝病等疾病。   作用机制 1.抑制肿瘤生

triptolide

释义   雷公藤甲素

例句   Objective It is to study the inducing H22 cell apoptosis action of triptolide.目的研究雷公藤甲素对H22细胞的诱导凋亡作用。

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