Mitochondria-targeted nitroxides exacerbate fluvastatin-mediated cytostatic and cytotoxic effects in breast cancer cells

作者：Cheng Gang; Lopez Marcos; Zielonka Jacek; Hauser Andrew D; Joseph Joy; McAllister Donna; Rowe J Jordi; Sugg Sonia L; Williams Carol L; Kalyanaraman Balaraman^*

来源：Cancer Biology and Therapy, 2011, 12(8): 707-717.

DOI：10.4161/cbt.12.8.16441

• breast cancer
• mitochondria-targeted antioxidants
• nitroxides
• reactive oxygen species
• statins

Mito-CP(11), 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-CP(11) alone and in combination with fluvastatin, a well known cholesterol lowering drug, in breast cancer cells. Mito-CP(11), but not CP or CP plus the cationic ligand, methyl triphenylphosphonium (Me-TPP(+)), inhibited MCF-7 breast cancer cell proliferation. Mito-CP(11) had only minimal effect on MCF-10A, non-tumorigenic mammary epithelial cells. Mito-CP(11), however, significantly enhanced fluvastatin-mediated cytotoxicity in MCF-7 cells. Mito-CP(11) alone and in combination with fluvastatin inhibited nuclear factor kappaB (NF kappa B) activity mainly in MCF-7 cells. We conclude that mitochondria-targeted nitroxide antioxidant molecules (such as Mito-CP(11)) 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.

• 出版日期2011-10-15