Clotrimazole inhibits cell proliferation in vitro and in vivo

Abstract

Cell proliferation is critically dependent on the regulated movement of ions across various cellular compartments. The antimycotic drug clotrimazole (CLT) has been shown to inhibit movement of Ca2+ and K+ across the plasma membrane. Our results show that CLT inhibits the rate of cell proliferation of normal and cancer cell lines in a reversible and dose-dependent manner in vitro. Moreover, CLT depletes the intracellular Ca2+ stores and prevents the rise in cytosolic Ca2+ that normally follows mitogenic stimulation. In mice with severe combined immunodeficiency disease (SCID) and inoculated intravenously with MM-RU human melanoma cells, daily subcutaneous injections of CLT induced a significant reduction in the number of lung metastases. Modulation of early ionic mitogenic signals and potent inhibition of cell proliferation both in vitro and in vivo are new and potentially useful clinical effects of CLT.

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

“…15,19,21,28 However, we observed that leukemic cells treated with clotrimazole consistently showed changes in their light-scattering properties like those caused by apoptosis-inducing antileukemic drugs. 50 The cells' decreased forward light scatter indicated reduced cell size, and their increased orthogonal light scatter indicated increased intracellular granularity (Figure 3).…”

“…Benzaquen et al 19 showed that clotrimazole inhibits in vitro proliferation of human melanoma, lung carcinoma, and colon carcinoma cell lines and inhibits metastasis of engrafted melanoma cells in immunodeficient mice. Khalid et al 28 and Smith et al 29 reported similar effects in glioblastoma and lung fibroblast cell lines, respectively.…”

“…Thapsigargin is an inhibitor of endoplasmic reticulum Ca 2+ pumps; it releases Ca 2+ from inositol 1,4,5-trisphosphate-sensitive Ca 2+ pools and disrupts the balance between Ca 2+ influx and efflux through the endoplamic reticulum membrane. 19,51 Preincubation with 10-50 m clotrimazole for 5 min abrogated the thapsigargin-mediated increase in cytosolic Ca 2+ (Figure 7), indicating that the intracellular stores sensitive to thapsigargin had been depleted by clotrimazole. …”

“…First, clotrimazole suppresses the proliferation of carcinoma and melanoma cell lines and blocks metastasis of melanoma in immunodeficient mice without evident systemic toxicity. 19 Second, clotrimazole has been shown to inhibit normal lymphocyte proliferation, 20,21 at least partially by blocking IK channels, 15,22 and it reportedly exerts beneficial effects in patients with rheumatoid arthritis. 23,24 Importantly, concentrations of clotrimazole and its metabolites that effectively interfere with Ca 2+ metabolism and block IK channels are achievable in vivo.…”

“…This effect was observed both in leukemic cell lines and in primary leukemic lymphoblasts sustained in vitro by bone marrow-derived stroma. Surprisingly, although clotrimazole was reported to inhibit cell proliferation of various cell types without apparent cytotoxicity, 15,19,21,28,29 its primary mechanism of action in ALL cells was induction of apoptosis.…”