Cancer Research and Therapy Center, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Curr Drug Targets. 2011 Dec;12(14):2079-90. doi: 10.2174/138945011798829357.
Tumor necrosis factor-related apoptosis-inducing ligand or Apo2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis upon binding to its death domain-containing transmembrane receptors. The preferential toxicity of TRAIL to cancer cells and the sparing of normal cells make it an ideal cancer therapeutic agent. TRAIL induces apoptosis via the extrinsic death receptor apoptotic pathway and activates the JNK, ERK, Akt and NF-κB signaling cascades. However, not all cancer cells are sensitive to TRAIL therapy. This may limit its efficacy in the clinic, although ways have already been identified to overcome resistance by combining TRAIL with chemotherapeutic and other biological agents. This review focuses on TRAIL receptor-targeting as anticancer therapy, the apoptotic signaling pathways induced by TRAIL receptors, the prognostic implications of TRAIL receptor expression and modulation by combination therapies. The mechanisms of TRAIL resistance and strategies to overcome drug resistance will also be addressed. Finally, the progress of TRAIL and DR4/DR5-specific agonistic antibodies in clinical trials and the development of new receptor-selective TRAIL variants are discussed including future directions for apoptosis inducing therapy.
肿瘤坏死因子相关凋亡诱导配体或 Apo2 配体（TRAIL/Apo2L）是肿瘤坏死因子（TNF）超家族的一员，与包含死亡结构域的跨膜受体结合后诱导细胞凋亡。TRAIL 对癌细胞的优先毒性和对正常细胞的保护作用使其成为理想的癌症治疗剂。TRAIL 通过外在的死亡受体凋亡途径诱导细胞凋亡，并激活 JNK、ERK、Akt 和 NF-κB 信号级联反应。然而，并非所有癌细胞对 TRAIL 治疗都敏感。这可能限制了它在临床上的疗效，尽管已经确定了通过将 TRAIL 与化疗和其他生物制剂联合使用来克服耐药性的方法。本文重点介绍 TRAIL 受体靶向作为抗癌治疗、TRAIL 受体诱导的凋亡信号通路、TRAIL 受体表达的预后意义以及联合治疗的调节。还将讨论 TRAIL 耐药的机制和克服耐药性的策略。最后，讨论了 TRAIL 和 DR4/DR5 特异性激动性抗体在临床试验中的进展以及新的受体选择性 TRAIL 变体的开发，包括诱导凋亡治疗的未来方向。
