Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria
| Autor: | D, Genini, S, Adachi, Q, Chao, D W, Rose, C J, Carrera, H B, Cottam, D A, Carson, L M, Leoni |
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| Rok vydání: | 2000 |
| Předmět: |
B-Lymphocytes
Time Factors Deoxyadenosines Microinjections Adenine Nucleotides Cell Survival Antineoplastic Agents Apoptosis DNA Mitochondrial Immunohistochemistry Leukemia Lymphocytic Chronic B-Cell Membrane Potentials Mitochondria Adenosine Triphosphate Tumor Cells Cultured Cladribine Humans Arabinonucleosides Comet Assay Vidarabine Clofarabine DNA Damage |
| Zdroj: | Blood. 96(10) |
| ISSN: | 0006-4971 |
| Popis: | Adenine deoxynucleosides induce apoptosis in quiescent lymphocytes and are thus useful drugs for the treatment of indolent lymphoproliferative diseases. To explain why deoxyadenosine and its analogs are toxic to a cell that is not undergoing replicative DNA synthesis, several mechanisms have been proposed, including the direct binding of dATP to the pro-apoptotic factor Apaf-1 and the activation of the caspase-9 and -3 pathways. In this study it is shown, by means of several assays on whole cells and isolated mitochondria, that 2-chloro-2'-deoxyadenosine (2CdA) and 2-choloro-2'-ara-fluorodeoxyadenosine (CaFdA) disrupt the integrity of mitochondria from primary chronic lymphocytic leukemia (B-CLL) cells. The nucleoside-induced damage leads to the release of the pro-apoptotic mitochondrial proteins cytochrome c and apoptosis-inducing factor. The other adenine deoxynucleosides tested displayed comparable DNA-damaging potency but did not affect mitochondrial function. Interference with mitochondrial integrity, thus, may be a factor in the potent cytotoxic effects of 2CdA and CaFdA toward nondividing lymphocytes. |
| Databáze: | OpenAIRE |
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