{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T20:26:31Z","timestamp":1786739191970,"version":"build-2736575974"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020]]},"abstract":"\n \n \n Thioridazine, belonging to first-generation antipsychotic drugs, is a prescription used to treat schizophrenia. However, the effect of thioridazine on intracellular Ca\n 2+<\/jats:sup>\n concentration ([Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n ) and viability in human liver cancer cells is unclear. This study examined whether thioridazine altered Ca\n 2+<\/jats:sup>\n signaling and viability in HepG2 human hepatocellular carcinoma cells. Ca\n 2+<\/jats:sup>\n concentrations in suspended cells were measured using the fluorescent Ca\n 2+<\/jats:sup>\n -sensitive dye fura-2. Cell viability was examined by WST-1 assay. Thioridazine at concentrations of 25\u2013100 \u03bcM induced [Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n rises. Ca\n 2+<\/jats:sup>\n removal reduced the signal by 20%. Thioridazine (100 \u03bcM) induced Mn\n 2+<\/jats:sup>\n influx suggesting of Ca\n 2+<\/jats:sup>\n entry. Thioridazine-induced Ca\n 2+<\/jats:sup>\n entry was inhibited by 20% by protein kinase C (PKC) activator (phorbol 12-myristate 13 acetate) and inhibitor (GF109203X) and by three inhibitors of store-operated Ca\n 2+<\/jats:sup>\n channels: nifedipine, econazole, and SKF96365. In Ca\n 2+<\/jats:sup>\n -free medium, treatment with the endoplasmic reticulum Ca\n 2+<\/jats:sup>\n pump inhibitor thapsigargin (TG) abolished thioridazine-evoked [Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n rises. On the other hand, thioridazine preincubation completely inhibited the [Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n rises induced by TG. Furthermore, U73122 totally suppressed the [Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n rises induced by thioridazine via inhibition of phospholipase C (PLC). Regarding cytotoxicity, at 30-80 \u03bcM, thioridazine reduced cell viability in a concentration-dependent fashion. This cytotoxicity was not prevented by preincubation with 1,2-bis (2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid-acetoxymethyl ester (BAPTA\/AM) (a Ca\n 2+<\/jats:sup>\n chelator). To conclude, thioridazine caused concentration-dependent [Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n rises in HepG2 human hepatoma cells by inducing Ca\n 2+<\/jats:sup>\n release from the endoplasmic reticulum via PLC-associated pathways and Ca\n 2+<\/jats:sup>\n influx from extracellular medium through PKC-sensitive store-operated Ca\n 2+<\/jats:sup>\n entry. In addition, thioridazine induced cytotoxicity in a Ca\n 2+<\/jats:sup>\n -independent manner.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.4103\/cjp.cjp_45_20","type":"journal-article","created":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T09:41:47Z","timestamp":1598521307000},"page":"187-194","source":"Crossref","is-referenced-by-count":6,"title":["Exploration of Thioridazine-Induced Ca2+ Signaling and non-Ca2+ -Triggered Cell Death in HepG2 Human Hepatocellular Carcinoma 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