死亡受体信号通路耐受机制及肿瘤治疗

Resistance mechanism in the death receptors mediated apoptosis signaling pathways and cancer therapy

死亡受体介导的凋亡通路是治疗肿瘤的理想方案。凋亡通路中具有复杂的调控机制,控制细胞的生死存亡。其中有多类抗凋亡因子,致使肿瘤细胞对凋亡信号耐受,使得凋亡在肿瘤治疗领域的应用受限。临床前体外细胞及裸鼠研究发现,单独靶向这些死亡受体或抗凋亡因子的药物或与传统化疗联合可以有效引起肿瘤细胞凋亡,但临床II期实验没有明显治疗效果。本综述总结分析多种抗凋亡因子产生的耐受机制以及靶向药物的研究现状,提出同时靶向死亡受体、c-FLIP及IAP是治疗肿瘤的理想方案。

Death receptors mediated apoptosis pathway is the ideal solution for the treatment of tumors. Apoptosis pathway with complex regulatory mechanism controlls cell survival or death. There are many kinds of anti-apoptotic factors that cause the resistance of tumor cells to apoptosis, and thus produce limited appli- cation in the field of apoptosis in cancer therapy. Preclinical studies in cultured tumor cells and mouse models studies have found that drugs targeting these death receptors or anti-apoptotic factors or in combination with traditional chemotherapy can effectively induce tumor cells apoptosis. However, clinical phase 2 studies have demonstrated limited efficacy. This review have summarized and analyzed the resistant mechanisms of a variety of anti-apoptotic factors and research status of targeted drugs. Multi-targets therapy at death receptors, c-FLIP and IAPs could be an ideal strategy for the tumor treatment.