Ca2+ Signaling and Cell Death Induced by Protriptyline in HepG2 Human Hepatoma Cells |
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Authors: | Jue‐Long Wang Chiang‐Ting Chou Kang Liu Wei‐Zhe Liang Jin‐Shiung Cheng Hong‐Tai Chang I‐Shu Chen Ti Lu Chun‐Chi Kuo Chia‐Cheng Yu Pochuen Shieh Daih‐Huang Kuo Fu‐An Chen Chung‐Ren Jan |
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Institution: | 1. Department of Rehabilitation, Kaohsiung Veterans General Hospital Tainan Branch, Tainan, Taiwan;2. Department of Nursing, Division of Basic Medical Sciences, Chang Gung Institute of Technology, Chia‐Yi, Taiwan;3. Chronic Diseases and Health Promotion Research Center, Chang Gung Institute of Technology, Chia‐Yi, Taiwan;4. Department of Anesthesia, Kaohsiung Veterans General Hospital Tainan Branch, Tainan, Taiwan;5. Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan;6. Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan;7. Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan;8. Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan;9. Department of Nursing, Tzu Hui Institute of Technology, Pingtung, Taiwan;10. Department of Pharmacy, Tajen University, Pingtung, Taiwan |
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Abstract: | The effect of protriptyline on Ca2+ physiology in human hepatoma is unclear. This study explored the effect of protriptyline on Ca2+]i and cytotoxicity in HepG2 human hepatoma cells. Protriptyline (50–150 μM) evoked Ca2+]i rises. 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+]i rises that involved Ca2+ entry through nifedipine‐sensitive Ca2+ channels and PLC‐dependent Ca2+ release from endoplasmic reticulum. Protriptyline induced Ca2+‐independent cell death. |
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Keywords: | Ca2+ Cytotoxicity Human Hepatoma Cells Phospholipase C Protriptyline |
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