title: The antidepressant fluoxetine induces necrosis by energy depletion and mitochondrial calcium overload.
abstract: Selective Serotonin Reuptake Inhibitor antidepressants, such as fluoxetine (Prozac), have been shown to induce cell death in cancer cells, paving the way for their potential use as cancer therapy. These compounds are able to increase cytosolic calcium concentration ([Ca2+]cyt), but the involved mechanisms and their physiological consequences are still not well understood. Here, we show that fluoxetine induces an increase in [Ca2+]cyt by emptying the endoplasmic reticulum (ER) through the translocon, an ER Ca2+ leakage structure. Our data also show that fluoxetine inhibits oxygen consumption and lowers mitochondrial ATP. This latter is essential for Ca2+ reuptake into the ER, and we postulated therefore that the fluoxetine-induced decrease in mitochondrial ATP production results in the emptying of the ER, leading to capacitative calcium entry. Furthermore, Ca2+ quickly accumulated in the mitochondria, leading to mitochondrial Ca2+ overload and cell death. We found that fluoxetine could induce an early necrosis in human peripheral blood lymphocytes and Jurkat cells, and could also induce late apoptosis, especially in the tumor cell line. These results shed light on fluoxetine-induced cell death and its potential use in cancer treatment.
authors.affiliation: INSERM U1218, Institut Bergonié, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Charles
authors.affiliation: INSERM U1218, Institut Bergonié, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Hammadi
authors.affiliation: Laboratory of Cellular and Molecular Physiology EA4667, Université de Picardie Jules Verne, SFR CAP-SANTE (FED 4231), Amiens, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Kischel
authors.affiliation: INSERM U1218, Institut Bergonié, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Delcroix
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Demaurex
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Cyril
authors.initials: C
authors.lastname: Castelbou
authors.affiliation: INSERM U1218, Institut Bergonié, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Vacher
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, UMR 5095, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Devin
authors.affiliation: INSERM U1045, Centre de Recherche Cardio-Thoracique, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ducret
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Paula
authors.initials: P
authors.lastname: Nunes
authors.affiliation: INSERM U1218, Institut Bergonié, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vacher
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D000071739:Calcium Release Activated Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D057054:Molecular Imaging; D009336:Necrosis / Q000139:chemically induced* / Q000378:metabolism*; D010101:Oxygen Consumption; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018687:Antidepressive Agents, Second-Generation; D000071739:Calcium Release Activated Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D005473:Fluoxetine; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D054801:Phosphoinositide Phospholipase C; D002118:Calcium
keywords: CRAC; calcium overload; cell death; fluoxetine; respiratory chain