title: Deciphering the Nongenomic, Mitochondrial Toxicity of Tamoxifens As Determined by Cell Metabolism and Redox Activity.
abstract: Tamoxifen is not only considered a very potent chemotherapeutic adjuvant for estrogen receptor positive breast cancers but also a very good chemo-preventive drug. Recently, there has been a rising amount of evidence for a nongenomic cytotoxicity of tamoxifen, even in estrogen receptor negative cells, which has greatly confounded researchers. Clinically, the side effects of tamoxifen can be very serious, ranging from liver steatosis to cirrhosis, tumorigenesis, or onset of porphyrias. Herein, we deciphered the nongenomic, mitochondrial cytotoxicity of tamoxifen in estrogen receptor positive MCF7 versus triple-negative MDA-MB-231 cells, employing the mitochondrial complex III quinoloxidizing-center inhibitor myxothiazol. We showed a role for hydroxyl-radical-mediated lipid peroxidation, catalyzed by iron, stemming from the redox interactions of tamoxifen quinoid metabolites with complex III, resulting in Fenton-capable reduced quinones. The role of tamoxifen semiquinone species in mitochondrial toxicity was also shown together with evidence of mitochondrial DNA damage. Tamoxifen caused an overall metabolic (respiratory and glycolytic) rate decrease in the Pasteur type MCF cells, while in the Warburg type MDA-MB-231 cells the respiratory rate was not significantly affected and the glycolytiv rate was significantly boosted. The nongenomic cytotoxicity of tamoxifens was hence associated with the metabolic phenotype and redox activity of the cells, as in the present paradigm of Pasteur MCF7s versus Warburg MDA-MB-231 cells. Our present findings call for caution in the use of the drugs, especially as a chemopreventive and/or in cases of iron overload diseases.
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, The Radium Hospital, Oslo University Hospital , Montebello, Oslo 0379, Norway.
authors.forename: Theodossis Athanassios
authors.initials: TA
authors.lastname: Theodossiou
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, and Department for Cellular Therapy, The Radium Hospital, Oslo University Hospital , Montebello, Oslo 0379, Norway.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Wälchli
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, The Radium Hospital, Oslo University Hospital , Montebello, Oslo 0379, Norway.
authors.forename: Cathrine Elisabeth
authors.initials: CE
authors.lastname: Olsen
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, The Radium Hospital, Oslo University Hospital , Montebello, Oslo 0379, Norway.
authors.forename: Ellen
authors.initials: E
authors.lastname: Skarpen
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, The Radium Hospital, Oslo University Hospital , Montebello, Oslo 0379, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Berg
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects*; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000633:toxicity*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D013629:Tamoxifen