{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:36:00Z","timestamp":1791171360832,"version":"4.1.0"},"reference-count":39,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The purine nucleoside 2-chlorodeoxyadenosine (CdA) is often used in leukemia therapy. Its efficacy, however, is compromised by the emergence of resistant cells. In the present study, 3 CdA-resistant cell lines were generated and characterized. Their ability to accumulate 2-chloroadenosine triphosphate (CdATP) varied, reflecting differences in activities of deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK). Nonetheless, the selected lines were uniformly resistant to CdA-induced apoptosis, as assessed by caspase activation and DNA fragmentation. In contrast, cytosols from resistant cells were capable of robust caspase activation when incubated in the presence of cytochrome c and dATP. Moreover, replacement of dATP with CdATP also resulted in caspase activation in the parental and some of the resistant cell lines. Strikingly, CdA-induced decreases in mitochondrial transmembrane potential and release of cytochrome c from mitochondria were observed in the parental cells but not in any resistant lines. The lack of cytochrome c release correlated with an increased ability of mitochondria from resistant cells to sequester free Ca2+. Consistent with this enhanced Ca2+buffering capacity, an early increase in cytosolic Ca2+after CdA treatment of parental cells but not resistant cells was detected. Furthermore, CdA-resistant cells were selectively cross-resistant to thapsigargin but not to staurosporine- or Fas-induced apoptosis. In addition, CdA-induced caspase-3 activation and DNA fragmentation were inhibited by the Ca2+ chelator BAPTA-AM in sensitive cells. Taken together, the data indicate that the mechanism of resistance to CdA may be dictated by changes in Ca2+-sensitive mitochondrial events.<\/jats:p>","DOI":"10.1182\/blood.v99.2.655","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T12:46:40Z","timestamp":1027774000000},"page":"655-663","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":51,"title":["Resistance of leukemic cells to 2-chlorodeoxyadenosine is due to a lack of calcium-dependent cytochrome c release"],"prefix":"10.1182","volume":"99","author":[{"given":"Joya","family":"Chandra","sequence":"first","affiliation":[{"name":"From the Institute for Environmental Medicine, Division of Toxicology, and Department of Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, 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Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freidoun","family":"Albertioni","sequence":"additional","affiliation":[{"name":"From the Institute for Environmental Medicine, Division of Toxicology, and Department of Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sten","family":"Orrenius","sequence":"additional","affiliation":[{"name":"From the Institute for Environmental Medicine, Division of Toxicology, and Department of Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021218011076000_B1","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1073\/pnas.93.4.1716","article-title":"The treatment of chronic progressive multiple sclerosis with cladribine.","volume":"93","author":"Beutler","year":"1996","journal-title":"Proc 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