Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt, Komturstr. 3a, 60528 Frankfurt, Germany.
Nat Rev Drug Discov. 2012 Feb 1;11(2):109-24. doi: 10.1038/nrd3627.
Evasion of apoptosis is one of the crucial acquired capabilities used by cancer cells to fend off anticancer therapies. Inhibitor of apoptosis (IAP) proteins exert a range of biological activities that promote cancer cell survival and proliferation. X chromosome-linked IAP is a direct inhibitor of caspases - pro-apoptotic executioner proteases - whereas cellular IAP proteins block the assembly of pro-apoptotic protein signalling complexes and mediate the expression of anti-apoptotic molecules. Furthermore, mutations, amplifications and chromosomal translocations of IAP genes are associated with various malignancies. Among the therapeutic strategies that have been designed to target IAP proteins, the most widely used approach is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist. Alternative strategies include transcriptional repression and the use of antisense oligonucleotides. This Review provides an update on IAP protein biology as well as current and future perspectives on targeting IAP proteins for therapeutic intervention in human malignancies.
细胞凋亡逃避是癌细胞用来抵御抗癌疗法的关键获得性能力之一。凋亡抑制蛋白（IAP）发挥一系列促进癌细胞存活和增殖的生物学活性。X 染色体连接的 IAP 是 caspase 的直接抑制剂 - 促凋亡执行蛋白酶 - 而细胞 IAP 蛋白阻止促凋亡蛋白信号复合物的组装，并介导抗凋亡分子的表达。此外，IAP 基因的突变、扩增和染色体易位与各种恶性肿瘤有关。在针对 IAP 蛋白设计的治疗策略中，应用最广泛的方法基于模拟第二线粒体衍生的半胱天冬酶激活剂（SMAC）的 IAP 结合基序，SMAC 作为内源性 IAP 拮抗剂起作用。替代策略包括转录抑制和使用反义寡核苷酸。这篇综述提供了关于 IAP 蛋白生物学的最新信息，以及针对人类恶性肿瘤中 IAP 蛋白治疗干预的当前和未来观点。
