期刊
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
卷 109, 期 2, 页码 103-110出版社
WILEY
DOI: 10.1111/j.1742-7843.2011.00690.x
关键词
-
资金
- Kaohsiung Veterans General Hospital [VGHKS99-098, VGHKS99-012]
The effect of sertraline, an antidepressant, on cytosolic-free Ca2+ levels ([Ca2+](i)) in human cancer cells is unclear. This study examined whether sertraline altered basal [Ca2+](i) levels in suspended PC3 human prostate cancer cells by using fura-2 as a Ca2+-sensitive fluorescent probe. At concentrations of 10-150 mu M, sertraline induced a [Ca2+](i) rise in a concentration-dependent fashion. The Ca2+ signal was reduced partly by removing extracellular Ca2+ indicating that Ca2+ entry and release both contributed to the [Ca2+](i) rise. Sertraline induced Mn2+ influx, leading to quench of fura-2 fluorescence suggesting Ca2+ influx. This Ca2+ influx was inhibited by the suppression of store-operated Ca2+ channels or by the modulation of protein kinase C activity. In Ca2+-free medium, pre-treatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin or 2,5-di-(t-butyl)-1,4-hydroquinone nearly abolished sertraline-induced Ca2+ release. Conversely, pre-treatment with sertraline greatly reduced the inhibitor-induced [Ca2+](i) rise, suggesting that sertraline released Ca2+ from the endoplasmic reticulum. Inhibition of phospholipase C inhibited sertraline-induced [Ca2+](i) rise. At 20-30 mu M, sertraline killed cells in a concentration-dependent manner. The cytotoxic effect of sertraline was enhanced by chelating cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM. Annexin V-FITC data suggest that sertraline (20 and 30 mu M) evoked apoptosis in a concentration-dependent manner. Together, in PC3 human prostate cancer cells, sertraline induced [Ca2+](i) rises by causing phospholipase C-dependent Ca2+ release from the endoplasmic reticulum and via multiple Ca2+ influx pathways that involve store-operated Ca2+ channels. Sertraline also induced apoptosis that was not triggered by [Ca2+](i) rise.
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