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In the present study, we tested the significance of mitochondria for apoptosis upon exposure to tamoxifen and etoposide using two human breast cancer cell lines, MCF-7 and MDA-MB-231. We showed that both tamoxifen and etoposide induced apoptosis, increased intramitochondrial calcium and nitric oxide, and decreased mitochondrial transmembrane potential in both cell lines. Both drugs increased mitochondrial protein tyrosine nitration and caused release of cytochrome c from the mitochondria of both cell lines. This study suggests that tamoxifen and etoposide utilize a common mechanism to induce apoptosis in MCF-7 and MDA-MB-231 cells.