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Carcinogenesis:中药阿可拉定抑制前列腺癌作用机理

来源/作者:alax   发表时间:2016-04-25 14:53:45  
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  国际知名肿瘤期刊《癌症发生》(Carcinogenesis, IF 5.334)近日发表了名为“阿可拉定通过IL-6/Stat3和极光激酶A信号通路抑制TRAMP小鼠的神经内分泌前列腺癌”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。

 

国际知名肿瘤期刊《癌症发生》(Carcinogenesis, IF 5.334)近日发表了名为“阿可拉定通过IL-6/Stat3和极光激酶A信号通路抑制TRAMP小鼠的神经内分泌前列腺癌”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。雄激素阻断治疗是前列腺癌的主流疗法,但几乎不可避免地产生耐药性。有理论认为,雄激素阻断疗法会刺激产生神经内分泌化(NED)细胞,这些细胞对传统化疗和抗激素类疗法都不敏感,并且会分泌大量的趋化因子、细胞因子(如IL-6)、生长因子等,同时伴随着原癌基因(如极光激酶A)的过表达,最终使疾病进展成为神经内分泌前列腺癌(NEPC)。此类患者缺乏有效治疗手段,预后极差,生存期往往不超过一年。

 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,能够抑制IL-6介导的LNCaP细胞系和TRAMP小鼠神经内分泌前列腺癌的发生发展。此前Yong教授课题组已发现,阿可拉定能够在雄激素受体(AR)阳性前列腺癌靶向作用于AR及其变异体AR-v7,促进其泛素化降解。其他研究者也发现阿可拉定在不同肿瘤中,如肝细胞癌、多发性骨髓瘤,通过调节IL-6/Stat3信号通路实现对肿瘤的抑制。

这项研究表明,在TRAMP小鼠模型中,阿可拉定能够诱导前列腺癌细胞凋亡,抑制其神经内分泌化,进而延长生存期,同时也显示出很好的药代动力学特征和安全性,并且能在前列腺组织有效富集。体内和体外研究均表明,阿可拉定能够抑制NED标志物突触素的表达,并且能够抑制IL-6/Stat3信号通路及原癌基因极光激酶A的高表达,这些都在机理层面解释了阿可拉定对NEPC的抑制作用。所以Yong教授课题组认为,阿可拉定有望成为NEPC新疗法,填补治疗学空白。
       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。目前阿可拉定已完成II期临床试验,达到预期目标,并于2015年9月提交新药证书申请,正在国家药监局审评中,有望获得有条件批准提前上市。

 

原文摘要:
Icaritin suppresses development of neuroendocrine differentiation of prostate cancer through inhibition of IL-6/STAT3 and Aurora kinase A pathways in TRAMP mice

Neuroendocrine prostate cancer (NEPC) has a poor prognosis, with a median survival of less than 1 year after diagnosis. Following androgen deprivation therapy, prostate adenocarcinoma cells have been observed to develop an androgen-receptor negative, terminally differentiated, and indolent neuroendocrine-like phenotype. However several molecular events, including interleukin 6 (IL-6) stimulation, in the prostate microenvironment result in the appearance of aggressive, highly proliferative castrate-resistant NEPC. In this study, we examined the mechanistic effects of a natural prenylflavonoid, icaritin (ICT), on neuroendocrine differentiation in IL-6-induced LNCaP cells, and NEPC development in the male transgenic adenocarcinoma of the mouse prostate (TRAMP) model. TRAMP mice received daily intraperitoneal injection of ICT or vehicle. ICT induced apoptosis in prostate tumor, suppressed NEPC development, and accordingly improved overall survival in TRAMP mice. Expression of neuroendocrine markers (synaptophysin) and androgen receptor in TRAMP mice and neuroendocrine-like LNCaP cells were inhibited by ICT. Suppression of neuroendocrine and NEPC development by ICT was associated with dose-dependent inhibitory effects on abnormally elevated IL-6/STAT3 and Aurora kinase A in vitro and in vivo. Since ICT demonstrated favourable pharmacokinetic and safety profiles with marked enrichment in prostate tissues, our study provide evidence for the development this prenylflavonoid as a multi-modal therapeutic agent against NEPC.

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