The effect of the anti-inflammatory compound NPC-14686 on intracellular Ca²⁺ concentration ([Ca²⁺](i)) and viability in OC2 human oral cancer cells was investigated. The Ca²⁺-sensitive fluorescent probe fura-2 was used to examine [Ca²⁺](i). NPC-14686 induced [Ca²⁺](i) rises in a concentration-dependent fashion. The effect was reduced approximately by 10% by removing extracellular Ca²⁺. NPC-14686- elicited Ca²⁺ signal was decreased by nifedipine, econazole, SKF96365, and GF109203X. In Ca²⁺-free medium, incubation with the endoplasmic reticulum Ca²⁺ pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) abolished NPC-14686-induced [Ca²⁺](i) rises. Conversely, pretreatment with NPC-14686 abolished thapsigargin or BHQ-induced [Ca²⁺](i) rises. Inhibition of phospholipase C with U73122 abolished NPC-14686-induced [Ca²⁺](i) rises. At 20-100 μM, NPC-14686 inhibited cell viability, which was not reversed by chelating cytosolic Ca²⁺ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acid-acetoxymethyl ester (BAPTA/AM). NPC-14686 between 20 μM and 40 μM also induced apoptosis. Collectively, in OC2 cells, NPC-14686 induced [Ca²⁺](i) rises by evoking phospholipase C-dependent Ca²⁺ release from the endoplasmic reticulum and Ca²⁺ entry via protein kinase C-regulated store-operated Ca²⁺ channels. NPC-14686 also caused Ca²⁺-independent apoptosis.