Effect of MK-886 on Ca2+ level and viability in PC3 human prostate cancer cells

Jong Khing Huang, Chorng Chih Huang, Ti Lu, Hong Tai Chang, Ko Long Lin, Jeng Yu Tsai, Wei Chuan Liao, Jau Min Chien, Chung Ren Jan*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

12 Scopus citations

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 languageEnglish
Pages (from-to)441-447
Number of pages7
JournalBasic and Clinical Pharmacology and Toxicology
Volume104
Issue number6
DOIs
StatePublished - 06 2009
Externally publishedYes

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