128 - Effects Beyond Mitochondria in Triple Negative Breast Cancer of Mitochondria-targeted SG1 Nitroxide

Abstract

Triple negative breast cancer (TNBC) is a harsh form of breast cancer that does not express estrogen (ER), progesterone (PR), and human epidermal growth factor (HER2) receptors. Currently, there is no effective therapy for TNBC. However, TNBC is characterized by mitochondrial dysfunction, elevated glycolysis, and increased generation of reactive oxygen species (ROS) as compared with receptor positive breast cancer cells. Then, targeting the biochemical differences between cancer and normal cell metabolism and mitochondrial bioenergetics with mitochondria-targeted nitroxides (MTNs) is a viable strategy. MTNs have been shown to exert selective cytotoxic effects in breast cancer but not in normal cells. Here, we tested the antitumor effects of Mito-SG1 [(N-tert-butyl- N-[1-diethylphosphono-(2,2-dimethylpropyl)] nitroxide conjugated to an alkyl triphenylphosphonium cation, in TNBC and normal breast epithelial cells. Mito-SG1 selectively induced a dose-dependent inhibition of cell viability and growth in TNBC and non-TNBC cells but not in normal MCF-10A cells. Treatment with Mito-SG1 also induced a concentration-dependent change in mitochondrial membrane potential and an increase in ROS production. We also established that Mito-SG1 targets mitochondria inducing a decrease in oxygen consumption rate (OCR), maximal respiration and spare respiratory capacity in TNBC and non-TNBC cells. Treatment with Mito-SG1 prompted a switch in both TNBC baseline and stressed metabolic phenotypes, suggesting that it impaired the cells' ability to meet their energetic and metabolic demands for survival by targeting mitochondria. Interestingly, we also found that Mito-SG1 effects extend beyond targeting mitochondria. Treatment of TNBC cells demonstrated that Mito-SG1 also impacts the Ras-MEK-ERK pathway, preventing downstream phosphorylation of kinases. Together, our results demonstrate that Mito-SG1 could be used as a novel alternative for the treatment of TNBC and that its effects outspread beyond targeting mitochondria.