title: Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria.
abstract: 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.
authors.affiliation: Department of Medicine and The Sam and Rose Stein Institute for Research on Aging, Whittier Diabetes Program, University of California, San Diego, La Jolla, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Genini
authors.forename: S
authors.initials: S
authors.lastname: Adachi
authors.forename: Q
authors.initials: Q
authors.lastname: Chao
authors.forename: D W
authors.initials: DW
authors.lastname: Rose
authors.forename: C J
authors.initials: CJ
authors.lastname: Carrera
authors.forename: H B
authors.initials: HB
authors.lastname: Cottam
authors.forename: D A
authors.initials: DA
authors.lastname: Carson
authors.forename: L M
authors.initials: LM
authors.lastname: Leoni
mesh_terms: D000227:Adenine Nucleotides; D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001087:Arabinonucleosides / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D017338:Cladribine / Q000494:pharmacology; D000077866:Clofarabine; D020552:Comet Assay; D004249:DNA Damage / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D003839:Deoxyadenosines / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D004272:DNA, Mitochondrial; D003839:Deoxyadenosines; D017338:Cladribine; D000077866:Clofarabine; D000255:Adenosine Triphosphate; D014740:Vidarabine; C024352:fludarabine