title: Effect of Antidepressant Doxepin on Ca²⁺ Homeostasis and Viability in PC3 Human Prostate Cancer Cells.
abstract: The effect of the antidepressant doxepin on cytosolic Ca²⁺ concentrations ([Ca²⁺](i)) and viability in PC3 human prostate cancer cells was explored. The Ca²⁺-sensitive fluorescent dye fura-2 was applied to measure [Ca²⁺](i). Doxepin at concentrations of 500-1000 μM induced a [Ca²⁺](i) rise in a concentration-dependent manner. The response was reduced partly by removing Ca²⁺. Doxepin-evoked Ca²⁺ entry was suppressed by Ca²⁺ entry blockers (nifedipine, econazole, SK&F96365), and protein kinase C (PKC) modulators. In the absence of extracellular Ca²⁺, incubation with the endoplasmic reticulum Ca²⁺ pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) partly inhibit doxepin-induced [Ca²⁺](i) rise. Incubation with doxepin nearly inhibited thapsigargin or BHQ-induced [Ca²⁺](i) rise. Inhibition of phospholipase C (PLC) with U73122 failed to alter doxepin-induced [Ca²⁺](i) rise. At concentrations of 200-250 μM, doxepin killed cells in a concentration-dependent manner. This cytotoxic effect was not reversed by chelating cytosolic Ca²⁺ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acid/acetoxy methyl (BAPTA/AM). Annexin V/PI staining data implied that doxepin (200 and 250 μM) did not induce apoptosis. Collectively, in PC3 cells, doxepin induced a [Ca²⁺](i) rise by evoking PLC-independent Ca²⁺ release from stores including the endoplasmic reticulum and Ca²⁺ entry via PKC-sensitive store-operated Ca²⁺ channels. Doxepin caused cell death that was independent of [Ca²⁺](i) rises.
authors.affiliation: Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, Republic of China.
authors.forename: Ti
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Nursing, Division of Basic Medical Sciences, Chang Gung Institute of Technology, Chia-Yi 61363, Taiwan, Republic of China.|Chronic Diseases and Health Promotion Research Center, Chang Gung Institute of Technology, Chia-Yi 61363, Taiwan, Republic of China.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chou
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, Republic of China.
authors.forename: Wei-Zhe
authors.initials: WZ
authors.lastname: Liang
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, Republic of China.
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, Republic of China.
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Chang
authors.affiliation: Department of Nursing, Tzu Hui Institute of Technology, Pingtung 92641, Taiwan, Republic of China.
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Division of Surgery, St. Joseph Hospital, Kaohsiung 80288, Taiwan, Republic of China.
authors.forename: Wei-Chuan
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 90741, Taiwan, Republic of China.
authors.forename: Daih-Huang
authors.initials: DH
authors.lastname: Kuo
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, Republic of China.
authors.forename: Chin-Man
authors.initials: CM
authors.lastname: Ho
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 90741, Taiwan, Republic of China.
authors.forename: Pochuen
authors.initials: P
authors.lastname: Shieh
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, Republic of China.
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004316:Doxepin / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D010738:Type C Phospholipases / Q000502:physiology
chemical_list: D000928:Antidepressive Agents; D004316:Doxepin; D010738:Type C Phospholipases; D002118:Calcium