Abstract
Despite advances in screening and treatment over the past several years, breast cancer remains a leading cause of cancer-related death among women in the United States. A major goal in breast cancer treatment is to develop safe and clinically useful therapeutic agents that will prevent the recurrence of breast cancers after front-line therapeutics have failed. Ideally, these agents would have relatively low toxicity against normal cells, and will specifically inhibit the growth and proliferation of cancer cells. Our group and others have previously demonstrated that breast cancer cells exhibit increased mitochondrial oxygen consumption compared with non-tumorigenic breast epithelial cells. This suggests that it may be possible to deliver redox active compounds to the mitochondria to selectively inhibit cancer cell metabolism. To demonstrate proof-of-principle, a series of mitochondria-targeted soft electrophiles (MTSEs) has been designed which selectively accumulate within the mitochondria of highly energetic breast cancer cells and modify mitochondrial proteins. A prototype MTSE, IBTP, significantly inhibits mitochondrial oxidative phosphorylation, resulting in decreased breast cancer cell proliferation, cell attachment, and migration in vitro. These results suggest MTSEs may represent a novel class of anti-cancer agents that prevent cancer cell growth by modification of specific mitochondrial proteins.
Highlights
It has long been known that cancer cells are metabolically distinct from normal cells
We hypothesized that mitochondriatargeted soft electrophiles (MTSEs) may represent a novel class of compounds which act by forming adducts with key metabolic proteins and inhibiting mitochondrial bioenergetics pathways
In order to characterize protein adduct formation by MTSEs in breast cancer cells, MB231 cells were treated with MTSE compounds over a dose-range from 0–5μM, and adduct formation was determined by Western blot analysis with quantification (Fig. 2)
Summary
It has long been known that cancer cells are metabolically distinct from normal cells. Many cancer cell types exhibit higher levels of glycolysis, irrespective of the levels of available oxygen needed for oxidative phosphorylation, a phenomenon known as “aerobic glycolysis” or the Warburg effect [1] This observation led to the concept that cancer cells have defective or disrupted mitochondrial metabolism. This study demonstrates that MTSEs cause profound inhibition of mitochondrial metabolism, and inhibit breast cancer cell proliferation, attachment, and migration; while non-tumorigenic MCF10A cells remain relatively insensitive. Taken together, these results suggest that modification of mitochondrial thiols by MTSEs alters metabolic pathways in breast cancer cells, and this class of compounds may be useful to inhibit the progression of highly energetic cancer cells
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