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Blood, 15 January 2002, Vol. 99, No. 2, pp. 655-663
NEOPLASIA
Resistance of leukemic cells to 2-chlorodeoxyadenosine is due to
a lack of calcium-dependent cytochrome c release
Joya Chandra,
Emma Mansson,
Vladimir Gogvadze,
Scott H. Kaufmann,
Freidoun Albertioni, and
Sten Orrenius
From the Institute for Environmental Medicine, Division
of Toxicology, and Department of Medicine, Division of Clinical
Pharmacology, Karolinska Institutet, Stockholm, Sweden.
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.
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