Paroxetine-induced Ca ²⁺ movement and death in OC2 human oral cancer cells

The effect of the antidepressant paroxetine on cytosolic free Ca ²⁺ concentrations ([Ca ²⁺ ] _i ) in OC2 human oral cancer cells is unclear. This study explored whether paroxetine changed basal [Ca ²⁺ ] _i levels in suspended OC2 cells by using fura-2 as a Ca ²⁺ -sensitive fluorescent dye. Paroxetine at concentrations between 100-1,000 μM increased [Ca ²⁺ ] _i in a concentration-dependent manner. The Ca ²⁺ signal was reduced by 50% by removing extracellular Ca ²⁺ . Paroxetine-induced Ca ²⁺ influx was inhibited by the store-operated Ca ²⁺ channel blockers nifedipine, econazole and SK&F96365, and protein kinase C modulators. In Ca ²⁺ -free medium, pretreatment with the endoplasmic reticulum Ca ²⁺ pump inhibitor thapsigargin abolished paroxetine-induced [Ca ²⁺ ] _i rise. Inhibition of phospholipase C with U73122 did not alter paroxetine-induced [Ca ²⁺ ] _i rise. Paroxetine at 10-50 μM induced cell death in a concentrationdependent manner. The death was not reversed when cytosolic Ca ²⁺ was chelated with 1,2-bis(2- aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Propidium iodide staining suggests that apoptosis plays a role in the death. Collectively, in OC2 cells, paroxetine induced [Ca ²⁺ ] _i rise by causing phospholipase C-independent Ca ²⁺ release from the endoplasmic reticulum and Ca ²⁺ influx via storeoperated Ca ²⁺ channels in a manner regulated by protein kinase C and phospholipase A2. Paroxetine (up to 50 μM) induced cell death in a Ca ²⁺ -independent manner.