title: Mitochondria-targeted nitroxides exacerbate fluvastatin-mediated cytostatic and cytotoxic effects in breast cancer cells.
abstract: Mito-CP11, a mitochondria-targeted nitroxide formed by conjugating a triphenylphosphonium cation to a five-membered nitroxide, carboxy-proxyl (CP), has been used as a superoxide dismutase (SOD) mimetic. In this study, we investigated the antiproliferative and cytotoxic properties of submicromolar levels of Mito-CP11 alone and in combination with fluvastatin, a well known cholesterol lowering drug, in breast cancer cells. Mito-CP11, but not CP or CP plus the cationic ligand, methyl triphenylphosphonium (Me-TPP+), inhibited MCF-7 breast cancer cell proliferation. Mito-CP11 had only minimal effect on MCF-10A, non-tumorigenic mammary epithelial cells. Mito-CP11, however, significantly enhanced fluvastatin-mediated cytotoxicity in MCF-7 cells. Mito-CP11 alone and in combination with fluvastatin inhibited nuclear factor kappa-B activity mainly in MCF-7 cells. We conclude that mitochondria-targeted nitroxide antioxidant molecules (such as Mito-CP11) that are non-toxic to non-tumorigenic cells could enhance the cytostatic and cytotoxic effects of statins in breast cancer cells. This strategy of combining mitochondria-targeted non-toxic molecules with cytotoxic chemotherapeutic drugs may be successfully used to enhance the efficacy of antitumor therapies in breast cancer treatment.
authors.affiliation: Department of Biophysics, Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.forename: Marcos
authors.initials: M
authors.lastname: Lopez
authors.forename: Jacek
authors.initials: J
authors.lastname: Zielonka
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hauser
authors.forename: Joy
authors.initials: J
authors.lastname: Joseph
authors.forename: Donna
authors.initials: D
authors.lastname: McAllister
authors.forename: J Jordi
authors.initials: JJ
authors.lastname: Rowe
authors.forename: Sonia L
authors.initials: SL
authors.lastname: Sugg
authors.forename: Carol L
authors.initials: CL
authors.lastname: Williams
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000008:administration & dosage / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009589:Nitrogen Oxides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D009589:Nitrogen Oxides; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D000077340:Fluvastatin; C039900:nitroxyl; D008798:Mevalonic Acid