Econazole induces increases in free intracellular Ca²⁺ concentrations in human osteosarcoma cells

Econazole is an antifungal drug with different in vitro effects. However, econazole's effect on osteoblast-like cells is unknown. In human MG63 osteosarcoma cells, the effect of econazole on intracellular Ca²⁺ concentrations ([Ca²⁺]_i) was explored by using fura-2. At a concentration of 0.1 μM, econazole started to cause a rise in [Ca ²⁺]_i in a concentration-dependent manner. Econazole-induced [Ca²⁺]_i rise was reduced by 74% by removal of extracellular Ca²⁺. The econazole-induced Ca²⁺ influx was mediated via a nimodipine-sensitive pathway. In Ca²⁺-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca ²⁺-ATPase, caused a [Ca²⁺]_i rise, after which the increasing effect of econazole on [Ca²⁺]_i was abolished. Pretreatment of cells with econazole to deplete Ca²⁺ stores totally prevented thapsigargin from releasing Ca²⁺. U73122, an inhibitor of phospholipase C, abolished histamine (an inositol 1,4,5-trisphosphate-dependent Ca²⁺ mobilizer)-induced, but not econazole-induced, [Ca²⁺]_i rise. Econazole inhibited 76% of thapsigargin-induced store-operated Ca²⁺ entry. These findings suggest that in MG63 osteosarcoma cells, econazole increases [Ca ²⁺]_i by stimulating Ca²⁺ influx and Ca ²⁺ release from the endoplasmic reticulum via a phospholipase C-independent manner. In contrast, econazole acts as a potent blocker of store-operated Ca²⁺ entry.