Role of antioxidant genes for the activity of artesunate against tumor cells.
The antimalaria drug, artesunate (ART), is very cytotoxic in tumor cell lines. The active moiety of ART is an endoperoxide bridge that generates carbon-centered free radicals and oxidative stress upon cleavage. Oxidative stress appears to be necessary for the antimalarial activity of ART. To test whether antioxidant gene expression affects the ART response in tumor cell lines we compared the baseline antioxidant mRNA gene expression in the 55 human tumor cell line panel from the National Cancer Institute Developmental Therapeutics Program to the ART IC50. Thioredoxin reductase expression showed a significant positive correlation to the ART IC50 and catalase expression was inversely correlated with the ART IC50 (p<0.05). WEHI7.2 mouse thymoma cells selected for resistance to hydrogen peroxide or transfected with thioredoxin, manganese superoxide dismutase, catalase or bcl-2 showed resistance to ART compared to the parental cell line. Taken together these data support a role for oxidative stress in the mechanism of ART action in tumor cells and suggest that antioxidant defenses act in combination to affect the cellular response to ART.
Efferth
Thomas
T
Center for Molecular Biology at the University of Heidelberg (ZMBH), 69120 Heidelberg, Germany. thomas.efferth@web.de
Briehl
Margaret M
MM
Tome
Margaret E
ME
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D002244:Carbon / Q000737:chemistry; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D013945:Thymoma / Q000378:metabolism; D014162:Transfection
D000975:Antioxidants; D037621:Artemisinins; D018076:DNA, Complementary; D012333:RNA, Messenger; D012717:Sesquiterpenes; D013879:Thioredoxins; D000077332:Artesunate; D002244:Carbon; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase