Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria.
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.
Genini
D
D
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.
Adachi
S
S
Chao
Q
Q
Rose
D W
DW
Carrera
C J
CJ
Cottam
H B
HB
Carson
D A
DA
Leoni
L M
LM
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
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D004272:DNA, Mitochondrial; D003839:Deoxyadenosines; D017338:Cladribine; D000077866:Clofarabine; D000255:Adenosine Triphosphate; D014740:Vidarabine; C024352:fludarabine