摘要
凋亡因子TRAIL(Tumor necrosis factor related apoptosis inducing ligand)能诱导肿瘤和转化细胞凋亡而不伤害正常细胞.TRAIL与细胞膜上死亡受体(death receptors,DR)结合,引发受体蛋白构象变化,经胞膜内受体死亡域(death domain,DD)募集接头蛋白FADD(Fas associateddeath domain),再经过FADD的死亡效应域(death effector domain,DED)与凋亡蛋白解酶原-8/10(procaspase-8/10)的DED相互结合,形成DISC(death-inducing signaling complex),引起凋亡蛋白解酶(caspase)级联反应,促使癌细胞凋亡.目前,可溶性重组人性化TRAIL(rhTRAIL)和抗DR4/5单克隆抗体已进入临床Ⅰ/Ⅱ期实验阶段.但绝大部分癌细胞对TRAIL有耐受或引起耐受,耐受机制主要是由于IAP(Inhibitor of Apoptosis Protein),Bcl-2(B-cell lymphoma-2)及cFLIP(cellular FLICE/caspase 8-like inhibitory protein,胞质凋亡抑制蛋白)家族蛋白的过表达而产生.因此,为了克服TRAIL的耐受,已有多种小分子IAP和Bcl-2拮抗剂在研发并进行临床实验.至今尚无cFLIP拮抗剂的报导.
TRAIL（Tumor necrosis factor related apoptosis inducing ligand） can induce apoptosis of broad spectrum of tumors and transformed cells,while sparing most normal cells.TRAIL binds to its death receptors（DR） to trigger a conformational change of receptor proteins.The death domain（DD） of the DR inside of the cell plasma membrane recruits FADD（Fas associated death domain） via the interaction of DD.Subsequently,DISC（death-inducing signaling complex） is formed through the DED：DED interaction between FADD and procaspase-8/10.Finally,apoptosis is induced through a cascade of caspase activation.The recombinatory human TRAIL and monoclonal antibodies of DR are currently under clinical phase I/II trials.However,a large number of cancers are resistant to TRAIL.The mechanisms of TRAIL resistance in tumor cells are mainly due to the over expression of IAP（Inhibitor of Apoptosis Protein）,cFLIP（cellular FLICE/caspase-8-like inhibitory protein） and Bcl-2（B-cell lymphoma-2） family proteins.Therefore,several small molecule antagonists for resistant proteins of IAP and Bcl-2,but not yet of cFLIP,have been discovered and currently under clinical trials to overcome the resistance.
出处
《昆明理工大学学报（自然科学版）》
CAS
北大核心
2012年第1期53-60,共8页
Journal of Kunming University of Science and Technology(Natural Science)
基金
云南省科技计划项目(项目编号:2011DH011)
