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: Gang Cheng, Jacek Zielonka, Donna McAllister, Micael Hardy, Olivier Ouari, Joy Joseph, Michael B Dwinell, Balaraman Kalyanaraman
• Journal: Cancer letters (Cancer Lett) Vol. 365 Issue 1 Pg. 96-106 (Aug 28 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 26004344 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Antioxidants
• Cations
• Cyclic N-Oxides
• Organophosphorus Compounds
• mito-carboxy proxyl
• Superoxides
• Adenosine Triphosphate
• Deoxyglucose
• Superoxide Dismutase

Topics

• Adenosine Triphosphate (metabolism)
• Antineoplastic Agents (pharmacology)
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Cations
• Cell Proliferation (drug effects)
• Cyclic N-Oxides (pharmacology)
• Deoxyglucose (pharmacology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Energy Metabolism (drug effects)
• Glycolysis (drug effects)
• Humans
• MCF-7 Cells
• Mitochondria (drug effects, metabolism, pathology)
• Neoplasms (metabolism, pathology)
• Organophosphorus Compounds (pharmacology)
• Signal Transduction (drug effects)
• Superoxide Dismutase (pharmacology)
• Superoxides (metabolism)
• Time Factors