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+)](i)) and cell viability in OC2 human oral cancer cells. [Ca(2+)](i) 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+)](i) 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+)](i) rises were substantially inhibited; and conversely, tamoxifen pretreatment inhibited a part of thapsigargin-induced [Ca(2+)](i) rises. Inhibition of phospholipase C with 2 microM U73122 did not change tamoxifen-induced [Ca(2+)](i) 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+)](i) 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+)](i) rise.
D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics; D020013:Calcium Signaling; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D006801:Humans; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D019284:Thapsigargin / Q000378:metabolism*
D002121:Calcium Channel Blockers; D020847:Estrogen Receptor Modulators; D013629:Tamoxifen; D019284:Thapsigargin; D011493:Protein Kinase C; D002118:Calcium