Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: Role of mitochondrial bioenergetics and energy-sensing mechanism. Issue 1 (28th August 2015)

• Record Type: Journal Article
• Authors: Cheng, Gang; Zielonka, Jacek; McAllister, Donna; Hardy, Micael; Ouari, Olivier; Joseph, Joy; Dwinell, Michael B.; Kalyanaraman, Balaraman
• Is Part Of: Cancer letters. Volume 365:Issue 1(2015)
• Page Start: 96
• Page End: 106
• Publication Date: 2015-08-28
• Subjects: ROS -- Superoxide -- Mitochondria -- Tumor cell proliferation -- Antioxidant -- 2-DG; 2-DG 2-deoxyglucose -- ECAR extracellular acidification rate -- Mito-CP mitochondria-targeted cationic carboxyproxyl nitroxide -- Mito-CP-Ac acetamide analog of Mito-CP lacking SOD-like activity -- MTAs mitochondria-targeted antioxidants -- OCR oxygen consumption rate -- PPR proton production rate; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.05.016
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Mitochondria-targeted antioxidants (MTAs) inhibit proliferation of cancer cells. Radical scavenging properties are not necessary for antiproliferative effects of MTAs. Inhibition of bioenergetic function is a common feature of different MTAs. 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.