title: Effect of sertraline on [Ca2+](i) and viability of human MG63 osteosarcoma cells.
abstract: The antidepressant, sertraline, has been shown to have diverse in vitro effects. This study examined whether sertraline altered [Ca(2+)](i) in MG63 human osteosarcoma cells by using fura-2 as a Ca(2+)-sensitive fluorescent dye. At 50-200 µM, sertraline induced a [Ca(2+)](i) rise in a concentration-dependent manner. Ca(2+) response was decreased by removing extracellular Ca(2+), suggesting that Ca(2+) entry and release contributed to the [Ca(2+)](i) signal. Sertraline-induced Ca(2+) entry was inhibited by nifedipine, La(3+), Gd(3+), and SK&F96365. When extracellular Ca(2+) was removed, pretreatment with the endoplasmic reticulum (ER) Ca(2+) pump inhibitor, thapsigargin, or 2,5-di-tert-butylhydroquinone (BHQ) abolished the sertraline-evoked [Ca(2+)](i) rise. Incubation with sertraline also abolished the thapsigargin or BHQ-induced [Ca(2+)](i) rise. Inhibition of phospholipase C (PLC) with U73122 abolished the sertraline-induced [Ca(2+)](i) rise. At 20-30 µM, overnight treatment with sertraline killed cells in a concentration-dependent manner. The cytotoxic effect of sertraline was not reversed by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Annexin V/propidium iodide staining data demonstrate that sertraline (30 µM) evoked apoptosis. Sertraline (20 and 30 µM) also increased levels of reactive oxygen species. Together, in human osteosarcoma cells, sertraline evoked a [Ca(2+)](i) rise by inducing PLC-dependent Ca(2+) release from the ER and Ca(2+) entry by L-type Ca(2+) channels and store-operated Ca(2+) channels. Sertraline induced cell death that may involve apoptosis by mitochondrial pathways.
authors.affiliation: Department of Rehabilitation, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Ko-Long
authors.initials: KL
authors.lastname: Lin
authors.forename: Chao-Chuan
authors.initials: CC
authors.lastname: Chi
authors.forename: Ti
authors.initials: T
authors.lastname: Lu
authors.forename: Li-Ling
authors.initials: LL
authors.lastname: Tseng
authors.forename: Jue-Long
authors.initials: JL
authors.lastname: Wang
authors.forename: Yi-Chau
authors.initials: YC
authors.lastname: Lu
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D020280:Sertraline / Q000008:administration & dosage / Q000494:pharmacology*; D019284:Thapsigargin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D002118:Calcium; D020746:Calcium Channels, L-Type; D004533:Egtazic Acid; D004963:Estrenes; D006873:Hydroquinones; D011760:Pyrrolidinones; D017382:Reactive Oxygen Species; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D019284:Thapsigargin; D010738:Type C Phospholipases; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C019359:2,5-di-tert-butylhydroquinone; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid