Theodossiou Theodossis Athanassios, Wälchli Sébastien, Olsen Cathrine Elisabeth, Skarpen Ellen, Berg Kristian
Department of Radiation Biology, Institute for Cancer Research, The Radium Hospital, Oslo University Hospital , Montebello, Oslo 0379, Norway.
Department of Cancer Immunology, Institute for Cancer Research, and Department for Cellular Therapy, The Radium Hospital, Oslo University Hospital , Montebello, Oslo 0379, Norway.
ACS Chem Biol. 2016 Jan 15;11(1):251-62. doi: 10.1021/acschembio.5b00734. Epub 2015 Nov 30.
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.
他莫昔芬不仅被认为是雌激素受体阳性乳腺癌非常有效的化疗辅助药物，也是一种非常好的化学预防药物。最近，越来越多的证据表明他莫昔芬具有非基因组细胞毒性，即使在雌激素受体阴性细胞中也是如此，这让研究人员大为困惑。临床上，他莫昔芬的副作用可能非常严重，从肝脂肪变性到肝硬化、肿瘤发生或卟啉症发作。在此，我们利用线粒体复合物III喹啉氧化中心抑制剂粘噻唑，解析了他莫昔芬在雌激素受体阳性的MCF7细胞与三阴性MDA-MB-231细胞中的非基因组线粒体细胞毒性。我们发现，他莫昔芬醌类代谢物与复合物III的氧化还原相互作用产生了具有芬顿反应能力的还原醌，铁催化了羟基自由基介导的脂质过氧化作用。还展示了他莫昔芬半醌类物质在线粒体毒性中的作用以及线粒体DNA损伤的证据。他莫昔芬导致巴斯德型MCF细胞的整体代谢（呼吸和糖酵解）速率下降，而在瓦伯格型MDA-MB-231细胞中，呼吸速率没有受到显著影响，糖酵解速率则显著提高。因此，他莫昔芬的非基因组细胞毒性与细胞的代谢表型和氧化还原活性有关，就像目前巴斯德型MCF7细胞与瓦伯格型MDA-MB-231细胞的范例一样。我们目前的研究结果提醒人们在使用这些药物时要谨慎，特别是作为化学预防药物和/或在铁过载疾病的情况下。
