Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase.

Nazarewicz RR, Zenebe WJ, Parihar A, Larson SK, Alidema E, Choi J, Ghafourifar P
Cancer Res. 2007 67 (3): 1282-90

PMID: 17283165 · DOI:10.1158/0008-5472.CAN-06-3099

Tamoxifen is an anticancer drug that induces oxidative stress and apoptosis via mitochondria-dependent and nitric oxide (NO)-dependent pathways. The present report shows that tamoxifen increases intramitochondrial ionized Ca(2+) concentration and stimulates mitochondrial NO synthase (mtNOS) activity in the mitochondria from rat liver and human breast cancer MCF-7 cells. By stimulating mtNOS, tamoxifen hampers mitochondrial respiration, releases cytochrome c, elevates mitochondrial lipid peroxidation, increases protein tyrosine nitration of certain mitochondrial proteins, decreases the catalytic activity of succinyl-CoA:3-oxoacid CoA-transferase, and induces aggregation of mitochondria. The present report suggests a critical role for mtNOS in apoptosis induced by tamoxifen.

MeSH Terms (19)

Animals Antineoplastic Agents, Hormonal Apoptosis Breast Neoplasms Calcium Cell Line, Tumor Cytochromes c Female Humans Lipid Peroxidation Mitochondria Mitochondria, Liver Nitric Oxide Synthase Oxidative Stress Oxygen Consumption Peroxynitrous Acid Rats Rats, Sprague-Dawley Tamoxifen

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