The antifungal antibiotic clotrimazole alters calcium homeostasis of leukemic lymphoblasts and induces apoptosis

Clotrimazole is an antimycotic imidazole derivative that interferes with cellular Ca2+ homeostasis. We investigated the effects of clotrimazole on acute lymphoblastic leukemia (ALL) cells. Treatment with 10 muM clotrimazole (a concentration achievable in vivo) reduced cell recovery from cultures of all nine ALL cell lines studied (B-lineage: OP-1, SUP-B15, RS4;11, NALM6, REH, and 380; T-lineage: MOLT4, CCRF-CEM, and CEM-C7). After 4 days of culture, median cell recovery was 10% (range, <1% to 37%) of cell recovery in parallel untreated cultures. Clotrimazole also inhibited recovery of primary ALL cells cultured on stromal feeder layers. After leukemic cells from 16 cases of ALL were cultured for 7 days with 10 muM clotrimazole, median cell recovery was <1% (range, <1% to 16%) of that in parallel untreated cultures. Clotrimazole was active against leukemic cells with genetic abnormalities associated with poor response to therapy and against multidrug-resistant cell lines. In contrast, mature T lymphocytes and bone marrow stromal cells were not affected. Clotrimazole induced depletion of intracellular Ca2+ stores in ALL cells, which was followed by apoptosis, as shown by annexin V binding and DNA fragmentation. Thus, clotrimazole is cytotoxic to ALL cells at concentrations achievable in vivo.