Document Detail

Does scavenging of mitochondrial superoxide attenuate cancer prosurvival signaling pathways?
MedLine Citation:
PMID:  23373855     Owner:  NLM     Status:  MEDLINE    
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.
Rafal R Nazarewicz; Anna Dikalova; Alfiya Bikineyeva; Sergey Ivanov; Igor A Kirilyuk; Igor A Grigor'ev; Sergey I Dikalov
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-03-20
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  19     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-07-01     Completed Date:  2014-01-31     Revised Date:  2014-10-10    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  344-9     Citation Subset:  IM    
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MeSH Terms
Apoptosis / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Mitochondria / drug effects*,  metabolism*
Neoplasms / metabolism*
Organophosphorus Compounds / pharmacology
Piperidines / pharmacology
Signal Transduction / drug effects
Superoxides / metabolism*
Grant Support
Reg. No./Substance:
0/MitoTEMPO; 0/Organophosphorus Compounds; 0/Piperidines; 11062-77-4/Superoxides

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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