Effect of nortriptyline on cytosolic Ca2+ regulation and viability in PC3 human prostate cancer cells |
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Authors: | Chih‐Chuan Pan Chen‐Fu Shaw Jong‐Khing Huang Chun‐Chi Kuo Daih‐Huang Kuo Pochuen Shieh Ti Lu Wei‐Chuan Chen Chin‐Man Ho Chung‐Ren Jan |
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Affiliation: | 1. Department of Psychiatry, Kaohsiung Veterans General Hospital, Taiwan 813;2. Department of Biological Sciences, National Sun Yat‐Sen University, Kaohsiung, Taiwan 900;3. Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 813;4. Department of Nursing, Tzu Hui Institute of Technology, Pingtung, Taiwan 926;5. Department of Pharmacy, Tajen University, Pingtung, Taiwan 907;6. Department of Surgery, Pingtung Christian Hospital, Pingtung, Taiwan 900;7. Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 813 |
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Abstract: | The effect of nortriptyline, a tricyclic antidepressant, on Ca2+ regulation and viability in human prostate cancer cells (PC3) is unclear. The present study examined whether nortriptyline altered basal [Ca2+]i levels in suspended PC3 cells using fura‐2 as a Ca2+‐sensitive fluorescent probe. Nortriptyline (50–500 µM) increased [Ca2+]i in a concentration‐dependent fashion. The Ca2+ signal was partially reduced by removing extracellular Ca2+, indicating that Ca2+ entry and release both contributed to the [Ca2+]i rise. Nortriptyline induced Mn2+ influx, leading to quench of fura‐2 fluorescence, suggesting Ca2+ influx. This Ca2+ influx was inhibited by activation of protein kinase C, but not by inhibition of L‐type Ca2+ channels. In Ca2+‐free medium, pretreatment with the endoplasmic reticulum Ca2+ pump inhibitor, thapsigargin nearly abolished nortriptyline‐induced Ca2+ release. Conversely, pretreatment with nortriptyline greatly reduced the inhibitor‐induced [Ca2+]i rise, suggesting that nortriptyline released Ca2+ from the endoplasmic reticulum. Inhibition of phospholipase C did not change the nortriptyline‐induced [Ca2+]i rise. Nortriptyline at a concentration of 10 µM increased viability in a Ca2+‐independent manner. At 50 µM, nortriptyline killed 45% of cells. Nortriptyline at 10 µM did not induce apoptosis, but at 50 µM induced significant apoptosis measured by propidium iodide staining. Together, in PC3 cells, nortriptyline induced [Ca2+]i rises by causing the phospholipase C‐independent Ca2+ release from the endoplasmic reticulum and Ca2+ influx via the protein kinase C‐sensitive pathway. Nortriptyline also induced both cell proliferation and death in a concentration‐dependent manner. Apoptosis was involved in the cell death. Drug Dev Res 71:323–330, 2010. © 2010 Wiley‐Liss, Inc. |
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Keywords: | apoptosis death nortriptyline PC3 cells prostate cancer |
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