Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase.
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.
Nazarewicz
Rafal R
RR
Vascular Surgery, Davis Heart and Lung Research Institute, and Institute of Mitochondrial Biology, Ohio State University Medical Center, 473 West 12th Avenue, Columbus, OH 43210, USA.
Zenebe
Woineshet J
WJ
Parihar
Arti
A
Larson
Sarah K
SK
Alidema
Enver
E
Choi
Jiho
J
Ghafourifar
Pedram
P
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D030421:Peroxynitrous Acid; D045304:Cytochromes c; D019001:Nitric Oxide Synthase; D002118:Calcium