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ORIGINAL ARTICLE
Year : 2020  |  Volume : 63  |  Issue : 4  |  Page : 187-194

Exploration of thioridazine-induced Ca2+ signaling and non-Ca2+-triggered cell death in HepG2 human hepatocellular carcinoma cells


1 Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
2 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung; Department of Pharmacy, Tajen University, Pingtung, Taiwan
3 Department of Rehabilitation, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
4 Department of Nursing, Tzu Hui Institute of Technology, Pingtung, Taiwan
5 Department of Endocrinology and Metabolism, Kaohsiung Veteran General Hospital Tainan Branch; Chung Hwa University of Medical and Technology, Tainan, Taiwan
6 Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chiayi Campus; Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital Chiayi Branch, Puzi City, Chiayi County, Taiwan
7 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

Correspondence Address:
Dr. Chiang-Ting Chou
Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chiayi Campus, Puzi City, Chiayi County
Taiwan
Dr. Chung-Ren Jan
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung
Taiwan
Dr. Lyh-Jyh Hao
Department of Metabolism, Kaohsiung Veterans General Hospital Tainan Branch, Tainan
Taiwan
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Source of Support: This work was supported by Kaohsiung Veterans General Hospital (VGHKS108-197) to I-Shu Chen., Conflict of Interest: None


DOI: 10.4103/CJP.CJP_45_20

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Thioridazine, belonging to first-generation antipsychotic drugs, is a prescription used to treat schizophrenia. However, the effect of thioridazine on intracellular Ca2+ concentration ([Ca2+]i) and viability in human liver cancer cells is unclear. This study examined whether thioridazine altered Ca2+ signaling and viability in HepG2 human hepatocellular carcinoma cells. Ca2+ concentrations in suspended cells were measured using the fluorescent Ca2+-sensitive dye fura-2. Cell viability was examined by WST-1 assay. Thioridazine at concentrations of 25–100 μM induced [Ca2+]i rises. Ca2+ removal reduced the signal by 20%. Thioridazine (100 μM) induced Mn2+ influx suggesting of Ca2+ entry. Thioridazine-induced Ca2+ 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 Ca2+ channels: nifedipine, econazole, and SKF96365. In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin (TG) abolished thioridazine-evoked [Ca2+]i rises. On the other hand, thioridazine preincubation completely inhibited the [Ca2+]i rises induced by TG. Furthermore, U73122 totally suppressed the [Ca2+]i rises induced by thioridazine via inhibition of phospholipase C (PLC). Regarding cytotoxicity, at 30-80 μM, 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 Ca2+ chelator). To conclude, thioridazine caused concentration-dependent [Ca2+]i rises in HepG2 human hepatoma cells by inducing Ca2+ release from the endoplasmic reticulum via PLC-associated pathways and Ca2+ influx from extracellular medium through PKC-sensitive store-operated Ca2+ entry. In addition, thioridazine induced cytotoxicity in a Ca2+-independent manner.


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