Elrod Heath A, Sun Shi-Yong
Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Cancer Biol Ther. 2008 Feb;7(2):163-73. doi: 10.4161/cbt.7.2.5335. Epub 2007 Nov 21.
Death receptors are important modulators of the extrinsic apoptotic pathway. Activating certain death receptors such as death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (i.e., DR4 and DR5) selectively kills cancer cells via induction of apoptosis while sparing normal cells. Thus, soluble recombinant TRAIL and agonistic antibodies to DR4 or DR5 have progressed to phase I and phase II clinical trials. Many cancer therapeutic drugs including chemotherapeutic agents have been shown to induce the expression or redistribution at the cell surface of death receptors including TRAIL death receptors. In addition, chemotherapeutic agents have also been shown to enhance induction of apoptosis by TRAIL or agonistic antibodies or overcome cell resistance to TRAIL or agonistic antibodies. Targeted induction of apoptosis by activation of the death receptor-mediated extrinsic apoptotic pathway should be an ideal therapeutic strategy to eliminate cancer cells. Therefore, death receptors, particularly TRAIL death receptors, have emerged as an important cancer therapeutic target. This article will focus on reviewing and discussing the modulation of death receptors by cancer therapeutic agents and its implications in cancer therapy.
死亡受体是细胞外凋亡途径的重要调节因子。激活某些死亡受体，如肿瘤坏死因子相关凋亡诱导配体（TRAIL）的死亡受体（即DR4和DR5），可通过诱导凋亡选择性地杀死癌细胞，同时使正常细胞免受影响。因此，可溶性重组TRAIL以及针对DR4或DR5的激动性抗体已进入I期和II期临床试验。包括化疗药物在内的许多癌症治疗药物已被证明可诱导死亡受体（包括TRAIL死亡受体）在细胞表面的表达或重新分布。此外，化疗药物还被证明可增强TRAIL或激动性抗体诱导的凋亡，或克服细胞对TRAIL或激动性抗体的抗性。通过激活死亡受体介导的细胞外凋亡途径来靶向诱导凋亡，应该是消除癌细胞的理想治疗策略。因此，死亡受体，尤其是TRAIL死亡受体，已成为重要的癌症治疗靶点。本文将重点回顾和讨论癌症治疗药物对死亡受体的调节及其在癌症治疗中的意义。
