摘要
肿瘤凋亡因子TRAIL(TNF-related apoptosis-inducing ligand)是TNF家族的成员之一,其不论在体内还是体外均可选择性诱导癌细胞凋亡。初期临床试验已经证实TRAIL或死亡受体激动剂抗体在癌症治疗中的安全性。另外,也有研究表明,许多癌细胞对TRAIL有耐受性,究其原因是凋亡通路中抗凋亡蛋白c-FLIP和IAP等的阻遏。更多研究发现,si RNA靶向抑制c-FLIP的同时结合广谱IAP拮抗剂AT406,进一步提高了TRAIL诱导的癌细胞凋亡,因此联合使用c-FLIP抑制剂或拮抗剂、IAP拮抗剂以及TRAIL或死亡受体激动剂抗体这三类药物可能是理想的抗癌新方法。综述了c-FLIP的发现、结构、功能和其参与死亡受体介导的信号通路,以及多种si RNA应用于c-FLIP以提高癌细胞对TRAIL敏感性和si RNA条件优化中的一些进展,并讨论了目前癌症临床治疗中si RNA的应用前景及存在的问题,最后提出较安全有效的基于TRAIL介导的癌症治疗新方法。
As a member of TNF superfamily, TRAIL（TNF-related apoptosis-inducing ligand） possesses a unique capacity to induce apoptosis selectively in cancer cells in vitro and in vivo. Early clinical trials have confirmed the safety of TRAIL and agonistic antibodies of death receptors（DR）. Moreover, most studies have shown that many cancer cells are resistant to TRAIL-induced apoptosis, because of the repression to cancer cell apoptosis by antiapoptotic proteins such as c-FLIP and IAPs（inhibitors of apoptosis protein）. Recent researches have demonstrated that the combined treatment of the down-regulating the expression of c-FLIP by si RNA and an IAP pan-antagonist AT406 profoundly enhanced the TRAIL induced apoptosis, suggesting that the above triple combination treatment may provide an ideal anti-cancer therapy. In this review, we summarized the discovery, structures, functions, and the role of c-FLIP in the DR mediated intracellular signaling pathways, corresponding progresses on the application of c-FLIP si RNA to TRAIL induced apoptosis of cancer cells and the optimized conditions of si RNA. And we also discussed the prospects and the existing problems of c-FLIP si RNA in the clinical application as a cancer therapy in vivo. Finally, we then proposed a safe and effective method for cancer therapy based on the TRAIL induced apoptosis.
出处
《生命的化学》
CAS
CSCD
2016年第5期715-721,共7页
Chemistry of Life
基金
国家自然科学基金项目(81360162
81260351)
