title: Does scavenging of mitochondrial superoxide attenuate cancer prosurvival signaling pathways?
abstract: It has been previously suggested that overexpression of mitochondrial superoxide dismutase (SOD) attenuates cancer development; however, the exact mechanism remains unclear. In this work, we have studied the direct effect of the mitochondria-targeted superoxide scavenger, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), on B16-F0 mouse melanoma cells and tumor growth in a nude mouse model of human melanoma. We show that scavenging of mitochondrial superoxide inhibited cell growth, reduced viability, and induced apoptosis in melanoma cells, but did not affect nonmalignant skin fibroblasts. Diminished mitochondrial superoxide inhibited redox-dependent Akt, restored activity of mitochondrial pyruvate dehydrogenase, and reduced HIF1-α and lactate dehydrogenase expression in cancer cells. Suppression of glycolysis in mitoTEMPO-treated melanoma cells resulted in a significant drop of cellular adenosine-5'-triphosphate and induced cell death. In vivo mitoTEMPO treatment effectively suppressed growth of established tumor in the mouse model of human melanoma. Therefore, our data lead to the hypothesis that scavenging of mitochondrial superoxide selectively inhibits redox-sensitive survival and metabolic pathways, resulting in cancer cell death. In contrast to existing anticancer therapies, inhibition of mitochondrial superoxide may represent a novel specific anticancer treatment with reduced cytotoxic side effects.
authors: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Rafal R
authors: RR
authors: Nazarewicz
authors: Anna
authors: A
authors: Dikalova
authors: Alfiya
authors: A
authors: Bikineyeva
authors: Sergey
authors: S
authors: Ivanov
authors: Igor A
authors: IA
authors: Kirilyuk
authors: Igor A
authors: IA
authors: Grigor'ev
authors: Sergey I
authors: SI
authors: Dikalov
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism*
chemical_list: C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D013481:Superoxides
references: FEBS Lett. 2005 May 9;579(12):2669-74
references: 15862307
references: Biochemistry (Mosc). 2008 Dec;73(12):1300-16
references: 19120016
references: Proc Natl Acad Sci U S A. 2010 May 11;107(19):8788-93
references: 20421486
references: Cancer Res. 2012 May 15;72(10):2634-44
references: 22431711
references: Free Radic Res. 2010 May;44(5):479-96
references: 20370557
references: Circ Res. 2010 Jul 9;107(1):106-16
references: 20448215
references: Cancer Res. 1979 Apr;39(4):1141-9
references: 217531
references: Am J Physiol Cell Physiol. 2002 Jun;282(6):C1212-24
references: 11997235
references: Cancer Biol Ther. 2011 Feb 15;11(4):383-94
references: 21150282