Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria

• Published in: Blood 2000-11, Vol.96 (10), p.3537-3543
• Main Authors: Genini, Davide, Adachi, Souichi, Chao, Qi, Rose, David W., Carrera, Carlos J., Cottam, Howard B., Carson, Dennis A., Leoni, Lorenzo M.
• Format: Article
• Language: English
• Subjects: Adenine Nucleotides; Adenosine Triphosphate - administration & dosage; Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - pharmacology; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Arabinonucleosides - pharmacology; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; B-Lymphocytes - ultrastructure; Biological and medical sciences; Cell Survival - drug effects; Chemotherapy; Cladribine - pharmacology; Clofarabine; Comet Assay; Deoxyadenosines - pharmacology; Deoxyadenosines - physiology; DNA Damage - physiology; DNA, Mitochondrial - drug effects; DNA, Mitochondrial - metabolism; Humans; Immunohistochemistry; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Medical sciences; Membrane Potentials - drug effects; Microinjections; Mitochondria - drug effects; Mitochondria - physiology; Mitochondria - ultrastructure; Pharmacology. Drug treatments; Time Factors; Tumor Cells, Cultured; Vidarabine - analogs & derivatives; Vidarabine - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V96.10.3537

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.