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.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenine Nucleotides
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Adenosine Triphosphate / administration & dosage
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Adenosine Triphosphate / analogs & derivatives
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Adenosine Triphosphate / pharmacology
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects*
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Arabinonucleosides / pharmacology
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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B-Lymphocytes / ultrastructure
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Cell Survival / drug effects
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Cladribine / pharmacology
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Clofarabine
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Comet Assay
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DNA Damage / physiology*
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DNA, Mitochondrial / drug effects
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DNA, Mitochondrial / metabolism
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Deoxyadenosines / pharmacology*
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Deoxyadenosines / physiology
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Humans
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Immunohistochemistry
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Membrane Potentials / drug effects
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Microinjections
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Mitochondria / drug effects*
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Mitochondria / physiology
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Mitochondria / ultrastructure
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Time Factors
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Tumor Cells, Cultured
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Vidarabine / analogs & derivatives*
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Vidarabine / pharmacology
Substances
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Adenine Nucleotides
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Antineoplastic Agents
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Arabinonucleosides
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DNA, Mitochondrial
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Deoxyadenosines
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Cladribine
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Clofarabine
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Adenosine Triphosphate
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Vidarabine
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fludarabine