Effect of MK‐886 on Ca2+ Level and Viability in PC3 Human Prostate Cancer Cells

: 3‐[1‐(p‐chlorobenzyl)‐5‐(isopropyl)‐3‐tert‐butylthioindol‐2‐yl]‐2, 2‐dimethylpropanoic acid (MK‐886) is widely used for inhibition of leucotriene synthesis in in vitro studies, however, many of its other effects have been reported. The present study investigated the effect of MK‐886 on cytosolic‐free Ca2+ concentrations ([Ca2+]i) and viability in human PC3 prostate cancer cells. [Ca2+]i in suspended cells was measured by using fura‐2. MK‐886 at concentrations of 1 µM and above increased [Ca2+]i in a concentration‐dependent manner with an EC50 value of 20 µM. The Ca2+ signal was reduced partly by removing extracellular Ca2+. MK‐886 evoked Mn2+ quenching of fura‐2 fluorescence, implicating Ca2+ entry. MK‐886‐induced Ca2+ influx was inhibited by store‐operated Ca2+ entry inhibitors nifedipine, econazole and SKF96365. In Ca2+‐free medium, after pre‐treatment with 10 µM MK‐886, 1 µM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor)‐induced [Ca2+]i rises were abolished; and conversely, thapsigargin pre‐treatment abolished MK‐886‐induced [Ca2+]i rises. Inhibition of phospholipase C with U73122 did not alter MK‐886‐induced [Ca2+]i rises. MK‐886 at concentrations of 1–100 µM concentration‐dependently decreased cell viability with an IC50 value of 60 µM. The cytotoxic effect of MK‐886 was not inhibited by pre‐chelating cytosolic Ca2+ with BAPTA/AM. Together, in PC3 cells, MK‐886 induced [Ca2+]i rises by causing phospholipase C‐independent Ca2+ release from the endoplasmic reticulum; and Ca2+ influx via store‐operated Ca2+ channels. Independently, MK‐886 was cytotoxic to cells in a Ca2+‐independent manner.