title: A novel class of mitochondria-targeted soft electrophiles modifies mitochondrial proteins and inhibits mitochondrial metabolism in breast cancer cells through redox mechanisms.
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.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Vayalil
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Joo-Yeun
authors.initials: JY
authors.lastname: Oh
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Fen
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Diers
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: M Ryan
authors.initials: MR
authors.lastname: Smith
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Hafez
authors.initials: H
authors.lastname: Golzarian
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Patsy G
authors.initials: PG
authors.lastname: Oliver
authors.affiliation: Department of Chemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Smith
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Sadanandan E
authors.initials: SE
authors.lastname: Velu
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Aimee
authors.initials: A
authors.lastname: Landar
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects
chemical_list: C456341:(4-iodobutyl)triphenylphosphonium; D024101:Mitochondrial Proteins; D009943:Organophosphorus Compounds