Induction of an apoptotic program in cell-free extracts by 2-chloro-2'-deoxyadenosine 5'-triphosphate and cytochrome c.
Induction of an apoptotic program in cell-free extracts by 2-chloro-2'-deoxyadenosine 5'-triphosphate and cytochrome c.
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DOI：
10.1073/pnas.95.16.9567
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发表时间：
1998-08
影响因子：
11.1
通讯作者：
L. Leoni;Q. Chao;H. Cottam;D. Genini;M. Rosenbach;C. Carrera;I. Budihardjo;Xiaodong Wang;D. Carson
中科院分区：
文献类型：
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作者：
L. Leoni;Q. Chao;H. Cottam;D. Genini;M. Rosenbach;C. Carrera;I. Budihardjo;Xiaodong Wang;D. Carson
腺嘌呤脱氧核苷，如2-氯-2 '-脱氧腺苷（2CdA）诱导静止淋巴细胞的凋亡，因此是治疗惰性淋巴组织增生性疾病的有用药物。然而，为什么脱氧腺苷及其类似物对没有进行复制DNA合成的细胞有毒，这仍然是令人困惑的。本实验证明，2CdA的5 '-三磷酸代谢物（2CdA-5'-triphosphate）类似于dATP，可以在无细胞系统中与细胞色素c和Apaf-1协同激活caspase-3。慢性淋巴细胞白血病细胞和正常外周血淋巴细胞均表达半胱天冬酶-3和凋亡蛋白酶激活因子1。孵育的淋巴细胞与2CdA诱导caspase-3的激活之前，DNA降解和细胞死亡。在DNA链断裂形成的背景下，2CdA-5 '-三磷酸对胱天蛋白酶蛋白水解级联的刺激可能为2CdA对非分裂淋巴细胞的强效细胞毒性作用提供解释。
Adenine deoxynucleosides, such as 2-chloro-2'-deoxyadenosine (2CdA) induce apoptosis in quiescent lymphocytes, and are thus useful drugs for the treatment of indolent lymphoproliferative diseases. However, it has remained puzzling why deoxyadenosine and its analogs are toxic to a cell that is not undergoing replicative DNA synthesis. The present experiments demonstrate that the 5'-triphosphate metabolite of 2CdA (2CdA-5'-triphosphate), similar to dATP, can cooperate with cytochrome c and Apaf-1 to activate caspase-3 in a cell free system. Chronic lymphocytic leukemia cells and normal peripheral blood lymphocytes expressed both caspase-3 and apoptotic protease activating factor 1. Incubation of the lymphocytes with 2CdA induced caspase-3 activation prior to DNA degradation and cell death. Stimulation of the caspase proteolytic cascade by 2CdA-5'-triphosphate, in the context of DNA strand break formation, may provide an explanation for the potent cytotoxic effects of 2CdA toward nondividing lymphocytes.