title: Ca2+Signaling and Cell Death Induced by Protriptyline in HepG2 Human Hepatoma Cells.
abstract: The effect of protriptyline on Ca2+physiology in human hepatoma is unclear. This study explored the effect of protriptyline on [Ca2+]iand cytotoxicity in HepG2 human hepatoma cells. Protriptyline (50-150 μM) evoked [Ca2+]irises. The Ca2+entry was inhibited by removal of Ca2+. Protriptyline-induced Ca2+entry was confirmed by Mn2+-induced quench of fura-2 fluorescence. Except nifedipine, econazole, SKF96365, GF109203X, and phorbol 12-myristate 13 acetate did not inhibit Ca2+entry. Treatment with the endoplasmic reticulum Ca2+pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) inhibited 40% of protriptyline-induced response. Treatment with protriptyline abolished BHQ-induced response. Inhibition of phospholipase C (PLC) suppressed protriptyline-evoked response by 70%. At 20-40 μM, protriptyline killed cells which was not reversed by the Ca2+chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Together, in HepG2 cells, protriptyline induced [Ca2+]irises that involved Ca2+entry through nifedipine-sensitive Ca2+channels and PLC-dependent Ca2+release from endoplasmic reticulum. Protriptyline induced Ca2+-independent cell death.
authors.affiliation: Department of Rehabilitation, Kaohsiung Veterans General Hospital Tainan Branch, Tainan, Taiwan.
authors.forename: Jue-Long
authors.initials: JL
authors.lastname: Wang
authors.affiliation: Department of Nursing, Division of Basic Medical Sciences, Chang Gung Institute of Technology, Chia-Yi, Taiwan.|Chronic Diseases and Health Promotion Research Center, Chang Gung Institute of Technology, Chia-Yi, Taiwan.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chou
authors.affiliation: Department of Anesthesia, Kaohsiung Veterans General Hospital Tainan Branch, Tainan, Taiwan.
authors.forename: Kang
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Wei-Zhe
authors.initials: WZ
authors.lastname: Liang
authors.affiliation: Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Jin-Shiung
authors.initials: JS
authors.lastname: Cheng
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Chang
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: I-Shu
authors.initials: IS
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, 813, Taiwan.
authors.forename: Ti
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Nursing, Tzu Hui Institute of Technology, Pingtung, Taiwan.
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung, Taiwan.
authors.forename: Pochuen
authors.initials: P
authors.lastname: Shieh
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung, Taiwan.
authors.forename: Daih-Huang
authors.initials: DH
authors.lastname: Kuo
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung, Taiwan.
authors.forename: Fu-An
authors.initials: FA
authors.lastname: Chen
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
mesh_terms: D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002118:Calcium / Q000819:agonists / Q000378:metabolism*; D002413:Cations, Divalent; D016923:Cell Death / Q000187:drug effects*; D004464:Econazole / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005456:Fluorescent Dyes; D016257:Fura-2; D056945:Hep G2 Cells; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects; D007700:Kinetics; D008301:Maleimides / Q000494:pharmacology; D008345:Manganese / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D011530:Protriptyline / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000929:Antidepressive Agents, Tricyclic; D002413:Cations, Divalent; D005456:Fluorescent Dyes; D006873:Hydroquinones; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C019359:2,5-di-tert-butylhydroquinone; D008345:Manganese; D011530:Protriptyline; D004533:Egtazic Acid; C016658:phorbolol myristate acetate; D004464:Econazole; D010738:Type C Phospholipases; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D009543:Nifedipine; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D016257:Fura-2
keywords: Ca2+; Cytotoxicity; Human Hepatoma Cells; Phospholipase C; Protriptyline