title: Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: Role of mitochondrial bioenergetics and energy-sensing mechanism.
abstract: One of the proposed mechanisms for tumor proliferation involves redox signaling mediated by reactive oxygen species such as superoxide and hydrogen peroxide generated at moderate levels. Thus, the antiproliferative and anti-tumor effects of certain antioxidants were attributed to their ability to mitigate intracellular reactive oxygen species (ROS). Recent reports support a role for mitochondrial ROS in stimulating tumor cell proliferation. In this study, we compared the antiproliferative effects and the effects on mitochondrial bioenergetic functions of a mitochondria-targeted cationic carboxyproxyl nitroxide (Mito-CP), exhibiting superoxide dismutase (SOD)-like activity and a synthetic cationic acetamide analog (Mito-CP-Ac) lacking the nitroxide moiety responsible for the SOD activity. Results indicate that both Mito-CP and Mito-CP-Ac potently inhibited tumor cell proliferation. Both compounds altered mitochondrial and glycolytic functions, and intracellular citrate levels. Both Mito-CP and Mito-CP-Ac synergized with 2-deoxy-glucose (2-DG) to deplete intracellular ATP, inhibit cell proliferation and induce apoptosis in pancreatic cancer cells. We conclude that mitochondria-targeted cationic agents inhibit tumor proliferation via modification of mitochondrial bioenergetics pathways rather than by dismutating and detoxifying mitochondrial superoxide.
authors.affiliation: Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Jacek
authors.initials: J
authors.lastname: Zielonka
authors.affiliation: Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: McAllister
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, 13397 Marseille, France.
authors.forename: Micael
authors.initials: M
authors.lastname: Hardy
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, 13397 Marseille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Ouari
authors.affiliation: Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Joseph
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Dwinell
authors.affiliation: Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: balarama@mcw.edu.
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002412:Cations; D049109:Cell Proliferation / Q000187:drug effects*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D002412:Cations; D003497:Cyclic N-Oxides; D009943:Organophosphorus Compounds; C571715:mito-carboxy proxyl; D013481:Superoxides; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D013482:Superoxide Dismutase
keywords: 2-DG; Antioxidant; Mitochondria; ROS; Superoxide; Tumor cell proliferation