Mitochondria-targeted nitroxides exacerbate fluvastatin-mediated cytostatic and cytotoxic effects in breast cancer cells. Cancer Biol Ther 2011 Oct 15;12(8):707-17
Date
07/30/2011Pubmed ID
21799303Pubmed Central ID
PMC3218525DOI
10.4161/cbt.12.8.16441Scopus ID
2-s2.0-80054116454 (requires institutional sign-in at Scopus site) 26 CitationsAbstract
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.
Author List
Cheng G, Lopez M, Zielonka J, Hauser AD, Joseph J, McAllister D, Rowe JJ, Sugg SL, Williams CL, Kalyanaraman BAuthors
Gang Cheng PhD Assistant Professor in the Biophysics department at Medical College of WisconsinBalaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Antineoplastic Combined Chemotherapy ProtocolsAntioxidants
Breast Neoplasms
Cell Line, Tumor
Drug Delivery Systems
Drug Synergism
Fatty Acids, Monounsaturated
Female
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Indoles
Mevalonic Acid
Mitochondria
Nitrogen Oxides
Organophosphorus Compounds
Reactive Oxygen Species
