Title | A novel class of mitochondria-targeted soft electrophiles modifies mitochondrial proteins and inhibits mitochondrial metabolism in breast cancer cells through redox mechanisms. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Vayalil, PK, Oh, J-Y, Zhou, F, Diers, AR, M Smith, R, Golzarian, H, Oliver, PG, Smith, RAJ, Murphy, MP, Velu, SE, Landar, A |
Journal | PLoS One |
Volume | 10 |
Issue | 3 |
Pagination | e0120460 |
Date Published | 2015 |
ISSN | 1932-6203 |
Keywords | Breast Neoplasms, Cell Adhesion, Cell Line, Tumor, Cell Movement, Cell Proliferation, Electron Transport, Energy Metabolism, Humans, Mitochondria, Mitochondrial Proteins, Organophosphorus Compounds, Protein Processing, Post-Translational |
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. |
DOI | 10.1371/journal.pone.0120460 |
Alternate Journal | PLoS ONE |
Citation Key | 10.1371/journal.pone.0120460 |
PubMed ID | 25785718 |
PubMed Central ID | PMC4364723 |
Grant List | MC_U105663142 / / Medical Research Council / United Kingdom HL096638 / HL / NHLBI NIH HHS / United States P30 CA013148 / CA / NCI NIH HHS / United States T32 HL007918 / HL / NHLBI NIH HHS / United States |