Kruyt Frank A E
Department of Medical Oncology, VU University Medical Center, CCA-Building, Room 2.36, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands.
Cancer Lett. 2008 May 8;263(1):14-25. doi: 10.1016/j.canlet.2008.02.003. Epub 2008 Mar 10.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors are promising targets for the selective eradication of tumor cells while sparing normal cells. Currently, both recombinant TRAIL proteins and TRAIL receptor agonistic antibodies are being tested in the clinic, showing encouraging antitumor activities and mild side effects. Unfortunately, resistance to TRAIL therapy is frequently encountered requiring combined treatments with sensitizing agents. Standard chemotherapeutics can enhance TRAIL sensitivity; however, more specific and less toxic agents are needed to exploit the full antitumor potential of TRAIL. Here, a brief overview of the TRAIL signaling pathway is given together with a short description of early results obtained with TRAIL therapy in the clinic. Mechanisms of TRAIL resistance and ways to overcome these by targeted agents that either neutralize apoptotic blockades or suppress prosurvival signals also triggered by TRAIL are highlighted, such as inhibitors of IAPs, Bcl-2 family members, HDACi, and modulators of NF-kappaB, Raf and EGFR signaling.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体是选择性根除肿瘤细胞而不损伤正常细胞的有前景的靶点。目前，重组TRAIL蛋白和TRAIL受体激动性抗体均正在临床中进行测试，显示出令人鼓舞的抗肿瘤活性和轻微的副作用。不幸的是，经常会遇到对TRAIL治疗的耐药性，这就需要与增敏剂联合治疗。标准化疗药物可增强TRAIL敏感性；然而，需要更具特异性且毒性更小的药物来充分发挥TRAIL的抗肿瘤潜力。在此，简要概述TRAIL信号通路，并简短描述TRAIL治疗在临床中获得的早期结果。还重点介绍了TRAIL耐药的机制以及通过靶向药物克服这些机制的方法，这些靶向药物可中和凋亡阻滞或抑制TRAIL引发的促生存信号，例如IAPs抑制剂、Bcl-2家族成员、HDACi以及NF-κB、Raf和EGFR信号通路的调节剂。
