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: Rafal R Nazarewicz, Anna Dikalova, Alfiya Bikineyeva, Sergey Ivanov, Igor A Kirilyuk, Igor A Grigor'ev, Sergey I Dikalov
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 19 Issue 4 Pg. 344-9 (Aug 01 2013) ISSN: 1557-7716 [Electronic] United States
• PMID: 23373855 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• MitoTEMPO
• Organophosphorus Compounds
• Piperidines
• Superoxides

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Humans
• Mice
• Mitochondria (drug effects, metabolism)
• Neoplasms (metabolism)
• Organophosphorus Compounds (pharmacology)
• Piperidines (pharmacology)
• Signal Transduction (drug effects)
• Superoxides (metabolism)