Abstract
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 1M and above increased [Ca2+]i in a concentration-dependent manner with an EC50 value of 20M. 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 Ca 2+ entry inhibitors nifedipine, econazole and SKF96365. In Ca 2+-free medium, after pre-treatment with 10M MK-886, 1M thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor)-induced [Ca 2+]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 [Ca 2+]i rises. MK-886 at concentrations of 1-100 M concentration-dependently decreased cell viability with an IC50 value of 60M. 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 endoplsmic reticulum; and Ca2+ influx via store-operated Ca2+ channels. Independently, MK-886 was cytotoxic to cells in a Ca2+-independent manner.
Original language | English |
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Pages (from-to) | 441-447 |
Number of pages | 7 |
Journal | Basic and Clinical Pharmacology and Toxicology |
Volume | 104 |
Issue number | 6 |
DOIs | |
State | Published - 06 2009 |
Externally published | Yes |