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Induction Of An Apoptotic Program In Cell-free Extracts By 2-chloro-2′-deoxyadenosine 5′-triphosphate And Cytochrome C

Lorenzo M. Leoni, Qi Chao, Howard B. Cottam, Davide Genini, Michael Rosenbach, Carlos J. Carrera, Imawati Budihardjo, Xiaodong Wang, Dennis A. Carson

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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 cytochromecand 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.