Tamoxifen-induced [Ca2+]i rises and Ca2+-independent cell death in human oral cancer cells.

The purpose of this study was to explore the effect of tamoxifen on cytosolic free Ca(2+) concentrations (Ca(2+)) and cell viability in OC2 human oral cancer cells. Ca(2+) and cell viability were measured by using the fluorescent dyes fura-2 and WST-1, respectively. Tamoxifen at concentrations above 2 microM increased Ca(2+) in a concentration-dependent manner. The Ca(2+) signal was reduced partly by removing extracellular Ca(2+). The tamoxifen-induced Ca(2+) influx was sensitive to blockade of L-type Ca(2+) channel blockers but insensitive to the estrogen receptor antagonist ICI 182,780 and protein kinase C modulators. In Ca(2+)-free medium, after pretreatment with 1 muM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor), tamoxifen-induced Ca(2+) rises were substantially inhibited; and conversely, tamoxifen pretreatment inhibited a part of thapsigargin-induced Ca(2+) rises. Inhibition of phospholipase C with 2 microM U73122 did not change tamoxifen-induced Ca(2+) rises. At concentrations between 10 and 50 microM tamoxifen killed cells in a concentration-dependent manner. The cytotoxic effect of 23 microM tamoxifen was not reversed by prechelating cytosolic Ca(2+) with BAPTA. Collectively, in OC2 cells, tamoxifen induced Ca(2+) rises, in a nongenomic manner, by causing Ca(2+) release from the endoplasmic reticulum, and Ca(2+) influx from L-type Ca(2+) channels. Furthermore, tamoxifen-caused cytotoxicity was not via a preceding Ca(2+) rise.