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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antioxidants / administration & dosage
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Antioxidants / chemistry
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Antioxidants / pharmacology
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Drug Delivery Systems
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Drug Synergism
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Fatty Acids, Monounsaturated / administration & dosage
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Fatty Acids, Monounsaturated / pharmacology*
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Female
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Fluvastatin
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
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Indoles / administration & dosage
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Indoles / pharmacology*
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Mevalonic Acid / administration & dosage
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Mevalonic Acid / pharmacology
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Mitochondria / pathology
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Nitrogen Oxides / administration & dosage
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Nitrogen Oxides / chemistry
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Nitrogen Oxides / pharmacology*
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Organophosphorus Compounds / administration & dosage
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Organophosphorus Compounds / chemistry
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Organophosphorus Compounds / pharmacology
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Reactive Oxygen Species / metabolism
Substances
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Antioxidants
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Fatty Acids, Monounsaturated
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Indoles
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Nitrogen Oxides
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Organophosphorus Compounds
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Reactive Oxygen Species
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Fluvastatin
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nitroxyl
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Mevalonic Acid