Oncotarget

Research Papers:

The antidepressant fluoxetine induces necrosis by energy depletion and mitochondrial calcium overload

Emilie Charles _, Mehdi Hammadi, Philippe Kischel, Vanessa Delcroix, Nicolas Demaurex, Cyril Castelbout, Anne-Marie Vacher, Anne Devin, Thomas Ducret, Paula Nunes and Pierre Vacher

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Oncotarget. 2017; 8:3181-3196. https://doi.org/10.18632/oncotarget.13689

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Abstract

Emilie Charles1,6,*, Mehdi Hammadi1,6,*, Philippe Kischel2, Vanessa Delcroix1,6, Nicolas Demaurex3, Cyril Castelbou3, Anne-Marie Vacher1,6, Anne Devin4,6, Thomas Ducret5,6, Paula Nunes3, Pierre Vacher1,6

1INSERM U1218, Institut Bergonié, Bordeaux, France

2Laboratory of Cellular and Molecular Physiology EA4667, Université de Picardie Jules Verne, SFR CAP-SANTE (FED 4231), Amiens, France

3Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland

4Institut de Biochimie et Génétique Cellulaires, UMR 5095, Bordeaux, France

5INSERM U1045, Centre de Recherche Cardio-Thoracique, Bordeaux, France

6Université de Bordeaux, Bordeaux, France

*These authors have contributed equally to this work

Correspondence to:

Mehdi Hammadi, email: [email protected]

Keywords: fluoxetine, CRAC, calcium overload, respiratory chain, cell death

Received: October 19, 2016    Accepted: November 21, 2016    Published: November 29, 2016

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.


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