A novel class of mitochondria-targeted soft electrophiles modifies mitochondrial proteins and inhibits mitochondrial metabolism in breast cancer cells through redox mechanisms.

TitleA novel class of mitochondria-targeted soft electrophiles modifies mitochondrial proteins and inhibits mitochondrial metabolism in breast cancer cells through redox mechanisms.
Publication TypeJournal Article
Year of Publication2015
AuthorsVayalil, PK, Oh, J-Y, Zhou, F, Diers, AR, M Smith, R, Golzarian, H, Oliver, PG, Smith, RAJ, Murphy, MP, Velu, SE, Landar, A
JournalPLoS One
Volume10
Issue3
Paginatione0120460
Date Published2015
ISSN1932-6203
KeywordsBreast 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.

DOI10.1371/journal.pone.0120460
Alternate JournalPLoS ONE
Citation Key10.1371/journal.pone.0120460
PubMed ID25785718
PubMed Central IDPMC4364723
Grant ListMC_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