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华裔学者Carcinogenesis发现

2018-12-03 14:43:32

华裔学者Carcinogenesis发现中药在癌症治疗中的新作用

国际知名肿瘤期刊《癌症发生》(Carcinogenesis, IF 5.266)近日发表了名为“前列腺癌治疗新方法:阿可拉定激活芳香碳氢化合物受体以靶向作用于雄激素受体及其变异异构体”的文章,该研究由新加坡国立大学医学院的Eu-Leong Yong教授课题组完成。

前列腺癌是一种激素刺激的疾病,在男性患者中属于高发癌种。由于患者人数众多,前列腺癌药物一直是药物研发的热门领域。目前针对雄激素敏感的前列腺癌已经可以被药物有效控制,但对雄激素不敏感的前列腺癌患者还有很大的临床需要未被满足。

雄激素受体(AR)信号通路持续激活是雄激素不敏感的前列腺癌疾病发展的重要因素,其中AR的C端缺失变异异构体(ARvs)起到关键作用。基于AR靶标已研发一系列药物如Enzalutamide和Abiraterone,但超过30%的前列腺癌人群很快产生耐药性,进一步研究发现其耐药性与ARvs中主要的变异异构体AR-v7有高度相关性,而针对AR-V7在临床上尚无有效药物,因此开发靶向AR-v7药物已成为国际药物研发热点。

芳香碳氢化合物受体(AhR)是一种胞质转录因子,在调节自身免疫与肿瘤免疫中起到重要作用。临床前研究及肿瘤患者组织研究表明,色氨酸(TRP)代谢物犬尿氨酸(KYN)与AhR的结合,会影响Nave CD4+ Th细胞的再分化选择,使其更倾向于分化成Treg细胞亚群,而非能够产生细胞因子IL-17的Th17细胞亚群。

Yong教授课题组研究首次发现,阿可拉定,一种天然的异戊烯类黄酮化合物,能够靶向作用于AR和AR-v7。阿可拉定通过结合AhR,促进AR和AR-v7的泛素化降解。在雄激素敏感和不敏感的前列腺癌小鼠模型中,阿可拉定均表现出对AR信号通路和肿瘤生长的抑制作用,且并无明显毒性。此篇文章认为阿可拉定有可能成为治疗AR阳性前列腺癌的全新药物分子。

阿可拉定是由北京珅奥基医药公司研制的中药/天然药物国家一类原创新药,具有完全自主知识产权,获得国家“十二五”重大新药创制项目支持,以及多家风险投资公司(如IDG、君联资本、启明资本、立达资本等)的注资。目前阿可拉定即将完成II期临床试验,已达预期目标,由于该药物在作用机理及生物标志物研究方面取得突破性进展,将于2015年6月以突破性疗法向国家药监局递交新药证书申请。

原文摘要:Persistent androgen receptor (AR) signaling is the key driving force behind progression and development of castration-resistant prostate cancer (CRPC). In many patients, AR COOH-terminal truncated splice variants (ARvs) play a critical role in contributing to the resistance against androgen depletion therapy. Unfortunately, clinically used antiandrogens like bicalutamide and enzalutamide, which target the ligand binding domain, have failed to suppress these AR variants. Here, we report for the first time that a natural prenylflavonoid, icaritin, can co-target both persistent AR and ARvs. Icaritin was found to inhibit transcription of key AR regulated genes, such as KLK3 (PSA) and ARvs regulated genes, such as UBE2C and induce apoptosis in AR-positive prostate cancer cells. Mechanistically, icaritin promoted the degradation of both AR and ARvs by binding to arylhydrocarbon-receptor (AhR) to mediate ubiquitin-proteasomal degradation. Therefore, icaritin impaired AR transactivation in prostate cancer cells. Knockdown of AhR gene restored AR stability and partially prevented icaritin-induced growth suppression. In clinically relevant murine models orthotopically implanted with androgen-sensitive and castration-resistant prostate cancer cells, icaritin was able to target AR and ARvs, to inhibit AR signaling, and tumor growth with no apparent toxicity. Our results provide a mechanistic framework for the development of icaritin, as a novel lead compound for AR-positive prostate cancer therapeutics, especially for those bearing AR splice variants.

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