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

Abstract

Clotrimazole is an antimycotic imidazole derivative that interferes with cellular Ca 2+ homeostasis. We investigated the effects of clotrimazole on acute lymphoblastic leukemia (ALL) cells. Treatment with 10 M 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, Ͻ1% 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 M clotrimazole, median cell recovery was Ͻ1% (range, Ͻ1% 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 Ca 2+ 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.

Cytotoxic copper(II), cobalt(II), zinc(II), and nickel(II) coordination compounds of clotrimazole

“…(2, 6, 10) and Ni II (4,8,12) complexes the μ eff values are in the range of 5.13-5.35 and 3.49-4.06 BM, respectively, which are also within the range for d 7 and d 8 complexes of these metals, respectively [21,22]. Table S1.…”

“…It has also been shown to promote the detachment of glycolytic enzymes from cytoskeleton decreasing the viability of Lewis lung carcinoma [3]. Furthermore, clotri has been proved to induce depletion of intracellular Ca 2+ stores in acute lymphoblastic leukemia (ALL) cells, which is then followed by apoptotic death at concentrations achievable in vivo [4].…”

Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia

“…For this purpose, we used bone marrow-derived mesenchymal cells to support the viability of leukemic cells. [45][46][47][48] Briefly, 2 Â 10 4 human mesenchymal cells immortalized by enforced expression of telomerase reverse transcriptase were plated on a 96-well tissue culture plate precoated with 1% gelatin. After 5 days, 1 Â 10 4 CD19 þ target cells (in case of cell lines) or 2 Â 10 5 CD19 þ target cells (in case of primary ALL cells) were plated on the wells and allowed to rest for 2 h. After extensive washing to remove residual IL-2-containing medium, receptor-transduced primary T cells were added to the wells at the proportion indicated in Results.…”

Clotrimazole Inhibits Hemoperoxidase of Plasmodium falciparum and Induces Oxidative Stress

“…Besides antifungal activity, CLT has diverse biological actions. It shows antiproliferative effect by acting as a translation initiation inhibitor (4), inhibits angiogenesis by blocking vascular endothelial growth factor expression (5), decreases glycolysis of lung carcinoma and colon adenocarcinoma cells (6), and induces apoptosis by altering calcium homeostasis of leukemic lymphoblasts (7). It is also known as an effective immunosuppressant (8,9).…”