Cyclosporin A induces apoptosis in childhood acute lymphoblastic leukemia cells.
In an effort to identify novel antileukemic agents that can bypass the mechanisms of multidrug resistance, we found that cyclosporin A ([CyA] 5 mumol/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 mumol/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 mumol/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 (e.g., 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 mumol/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.
Ito
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Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis 38105, USA.
Ribeiro
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RC
Behm
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Raimondi
S C
SC
Pui
C H
CH
Campana
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D000293:Adolescent; D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007223:Infant; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D016572:Cyclosporine