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Cyclosporin A Induces Apoptosis in Childhood Acute
Lymphoblastic Leukemia Cells
Chikako Ito,
Raul C. Ribeiro,
Frederick G. Behm,
Susana C. Raimondi,
Ching-Hon Pui, and
Dario Campana
From the Departments of Hematology-Oncology and Pathology and
Laboratory Medicine, St Jude Children's Research Hospital, Memphis;
and University of Tennessee College of Medicine, Memphis, TN.
In an effort to identify novel antileukemic agents that can bypass
the mechanisms of multidrug resistance, we found that cyclosporin A
([CyA] 5 µmol/L) produced a median cell kill of 69% (range, 47%
to 85%) in seven B-lineage acute lymphoblastic leukemia (ALL) cell
lines (OP-1, SUP-B15, KOPN-55bi, RS4;11, NALM6, REH, and 380) and three
T-lineage ALL cell lines (MOLT4, CCRF-CEM, and CEM-C7) after 4 days of
culture. At 10 µmol/L, median CyA toxicity was 99% (range, 88% to
>99%). CyA was equally toxic to both a multidrug-resistant cell
line, CEM-VLB100, which overexpresses gp-170
P-glycoprotein, and one resistant to topoisomerase II inhibitors, CEM-VM1-5, which has a mutation in the topoisomerase II gene. CyA was
also toxic to primary leukemic cells maintained in stroma-based culture, a system that substantially prolongs in vitro cell survival. Against lymphoblasts from 21 patients with B-lineage ALL, the compound
(at 5 µmol/L) reduced the leukemic cell number by a median of 87%
(range, 27% to >99%) compared with results for parallel control
cultures lacking CyA. Seven of these samples were from cases with
unfavorable genetic features (eg, Philadelphia-chromosome or
MLL gene rearrangements); three were obtained at relapse.
Against T lymphoblasts (from six patients), the median reduction in
cell number was 79% (range, 30% to >99%). At 10 µmol/L, the cell
kill exceeded 97% in all cases studied. The mechanism of CyA
cytotoxicity was found to be the activation of apoptosis, which was
suppressed by phorbol myristate acetate but not by inhibitors of
ceramide-mediated apoptosis, phosphatidyl inositol-3 kinase activity,
or tyrosine kinase activity. These findings demonstrate high levels of
CyA-induced toxicity against ALL cells at concentrations achievable in
vivo, thus providing a strong rationale for clinical testing of this agent in patients with ALL.
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 1001-1007
© 1998 by The American Society of Hematology.
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