Abstract

The antidepressant, sertraline, has been shown to have diverse in vitro effects. This study examined whether sertraline altered [Ca2+]i in MG63 human osteosarcoma cells by using fura-2 as a Ca2+-sensitive fluorescent dye. At 50–200 µM, sertraline induced a [Ca2+]i rise in a concentration-dependent manner. Ca2+ response was decreased by removing extracellular Ca2+, suggesting that Ca2+ entry and release contributed to the [Ca2+]i signal. Sertraline-induced Ca2+ entry was inhibited by nifedipine, La3+, Gd3+, and SK&F96365. When extracellular Ca2+ was removed, pretreatment with the endoplasmic reticulum (ER) Ca2+ pump inhibitor, thapsigargin, or 2,5-di-tert-butylhydroquinone (BHQ) abolished the sertraline-evoked [Ca2+]i rise. Incubation with sertraline also abolished the thapsigargin or BHQ-induced [Ca2+]i rise. Inhibition of phospholipase C (PLC) with U73122 abolished the sertraline-induced [Ca2+]i rise. At 20–30 µM, overnight treatment with sertraline killed cells in a concentration-dependent manner. The cytotoxic effect of sertraline was not reversed by chelating cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid (BAPTA). Annexin V/propidium iodide staining data demonstrate that sertraline (30 µM) evoked apoptosis. Sertraline (20 and 30 µM) also increased levels of reactive oxygen species. Together, in human osteosarcoma cells, sertraline evoked a [Ca2+]i rise by inducing PLC-dependent Ca2+ release from the ER and Ca2+ entry by L-type Ca2+ channels and store-operated Ca2+ channels. Sertraline induced cell death that may involve apoptosis by mitochondrial pathways.

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