Chlorzoxazone is a skeletal muscle relaxant. However, the effect of chlorzoxazone on intracellular Ca concentrations ([Ca]) in oral cancer cells is unclear. This study examined whether chlorzoxazone altered Ca signaling and cell viability in OC2 human oral cancer cells. [Ca]in suspended cells was measured using the fluorescent Ca-sensitive dye fura-2. Cell viability was examined by water-soluble tetrazolium-1 assay. Chlorzoxazone (250-1000 μM) induced [Ca]rises in a concentration-dependent manner. Ca removal reduced the signal by approximately 50%. Mn has been shown to enter cells through similar mechanisms as Ca but quenches fura-2 fluorescence at all excitation wavelengths. Chlorzoxazone (1000 μM) induced Mn influx, suggesting that Ca entry occurred. Chlorzoxazone-induced Ca entry was inhibited by 20% by inhibitors of store-operated Ca channels and protein kinase C (PKC) modulators. In Ca-free medium, treatment with the endoplasmic reticulum Ca pump inhibitor thapsigargin (TG) inhibited chlorzoxazone-evoked [Ca]rises by 88%. Conversely, treatment with chlorzoxazone-suppressed TG-evoked [Ca]rises 75%. Chlorzoxazone induced [Ca]rises by exclusively releasing Ca from the endoplasmic reticulum. Inhibition of phospholipase C (PLC) with U73122 did not alter chlorzoxazone-induced [Ca]rises. PLC activity was not involved in chlorzoxazone-evoked [Ca]rises. Chlorzoxazone at 200-700 μM decreased cell viability, which was not reversed by pretreatment with Ca chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/acetoxy methyl. In sum, in OC2 cells, chlorzoxazone induced [Ca]rises by evoking PLC-independent Ca release from the endoplasmic reticulum and Ca entry via PKC-sensitive store-operated Ca entry. Chlorzoxazone also caused Ca-independent cell death. Since [Ca]rises play a triggering or modulatory role in numerous cellular phenomena, the effect of chlorzoxazone on [Ca]and cell viability should be taken into account in other in vitro studies.
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