Department of Experimental Hematology, Medical University of Lodz, Poland.
Curr Mol Med. 2011 Nov;11(8):633-49. doi: 10.2174/156652411797536723.
Apoptosis, a programmed cell death, plays a key role in the regulation of tissue homeostasis. However, impairment of its regulation may promote formation and progression of malignancy. An important part of the apoptotic machinery are the inhibitor of apoptosis protein (IAP) family, regulating caspase activity, cell division or cell survival pathways through binding to their baculovirus AIP repeat (BIR) domains and/or by their ubiquitin-ligase RING zinc finger (RZF) activity. The following IAPs have been described so far: NAIP (neuronal apoptosis inhibitory protein; BIRC1), cIAP1 and cIAP2 (cellular inhibitor of apoptosis 1 and 2; BIRC2 and BIRC3, respectively), XIAP (X-chromosome binding IAP; BIRC4), survivin (BIRC5), BRUCE (Apollon; BIRC6), livin (BIRC7) and Ts-IAP (testis-specific IAP; BIRC8). Several studies suggested a potential contribution of IAPs to oncogenesis and resistance to anti-tumor treatment. Increased IAP expression was found in variety of human cancers, including hematological malignancies, such as leukemias and B-cell lymphomas. A correlation between the progression of those diseases and high levels of survivin or XIAP has been reported. Overexpression of XIAP in acute myeloid leukemia or survivin in acute lymphoblastic leukemia and diffuse large B-cell lymphoma have been indicated as an unfavorable prognostic factors. Elevated cellular levels of cIAP1, cIAP2, XIAP and survivin correlated with a progressive course of chronic lymphocytic leukemia. Thus, targeting IAPs with small-molecule inhibitors by their antisense approaches or natural IAP antagonist mimetics, may be an attractive strategy of anti-cancer treatment. Such agents can either directly induce apoptosis of tumor cells or sensitize them to other cytotoxic agents, hence overcoming drug-resistance. This review demonstrates the current knowledge on IAP molecular biology, as well as the mechanisms of action and the development of IAP-targeting agents for treatment of hematological malignancies.
细胞凋亡是一种程序性细胞死亡，在组织稳态的调节中起着关键作用。然而，其调节的损伤可能会促进恶性肿瘤的形成和进展。凋亡机制的一个重要组成部分是凋亡抑制蛋白（IAP）家族，通过结合它们的杆状病毒 AIP 重复（BIR）结构域和/或通过它们的泛素连接酶 RING 锌指（RZF）活性，调节半胱天冬酶活性、细胞分裂或细胞存活途径。到目前为止，已经描述了以下 IAP：NAIP（神经元凋亡抑制蛋白；BIRC1）、cIAP1 和 cIAP2（细胞凋亡抑制剂 1 和 2；BIRC2 和 BIRC3）、XIAP（X 染色体结合 IAP；BIRC4）、存活素（BIRC5）、BRUCE（阿波罗；BIRC6）、livin（BIRC7）和 Ts-IAP（睾丸特异性 IAP；BIRC8）。一些研究表明 IAP 对肿瘤发生和对肿瘤治疗的耐药性有潜在贡献。在包括血液恶性肿瘤在内的多种人类癌症中发现了 IAP 表达增加，例如白血病和 B 细胞淋巴瘤。已经报道了这些疾病的进展与存活素或 XIAP 水平升高之间的相关性。在急性髓系白血病中 XIAP 的过表达或在急性淋巴细胞白血病和弥漫性大 B 细胞淋巴瘤中存活素的过表达被认为是不利的预后因素。cIAP1、cIAP2、XIAP 和存活素的细胞水平升高与慢性淋巴细胞白血病的进行性病程相关。因此，通过反义方法或天然 IAP 拮抗剂模拟物靶向 IAP 的小分子抑制剂可能是一种有吸引力的抗癌治疗策略。这些药物可以直接诱导肿瘤细胞凋亡，或使它们对其他细胞毒性药物敏感，从而克服耐药性。本综述展示了 IAP 分子生物学的最新知识，以及 IAP 靶向药物治疗血液恶性肿瘤的作用机制和发展。
