Document Detail


The role of heme and the mitochondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarials.
MedLine Citation:
PMID:  21059641     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The artemisinin compounds are the frontline drugs for the treatment of drug-resistant malaria. They are selectively cytotoxic to mammalian cancer cell lines and have been implicated as neurotoxic and embryotoxic in animal studies. The endoperoxide functional group is both the pharmacophore and toxicophore, but the proposed chemical mechanisms and targets of cytotoxicity remain unclear. In this study we have used cell models and quantitative drug metabolite analysis to define the role of the mitochondrion and cellular heme in the chemical and molecular mechanisms of cell death induced by artemisinin compounds. HeLa ρ(0) cells, which are devoid of a functioning electron transport chain, were used to demonstrate that actively respiring mitochondria play an essential role in endoperoxide-induced cytotoxicity (artesunate IC(50) values, 48 h: HeLa cells, 6 ± 3 μM; and HeLa ρ(0) cells, 34 ± 5 μM) via the generation of reactive oxygen species and the induction of mitochondrial dysfunction and apoptosis but do not have any role in the reductive activation of the endoperoxide to cytotoxic carbon-centered radicals. However, using chemical modulators of heme synthesis (succinylacetone and protoporphyrin IX) and cellular iron content (holotransferrin), we have demonstrated definitively that free or protein-bound heme is responsible for intracellular activation of the endoperoxide group and that this is the chemical basis of cytotoxicity (IC(50) value and biomarker of bioactivation levels, respectively: 10β-(p-fluorophenoxy)dihydroartemisinin alone, 0.36 ± 0.20 μM and 11 ± 5%; and with succinylacetone, >100 μM and 2 ± 5%).
Authors:
Amy E Mercer; Ian M Copple; James L Maggs; Paul M O'Neill; B Kevin Park
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-08
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-10     Completed Date:  2011-03-02     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  987-96     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Antimalarials / chemistry,  toxicity*
Apoptosis / drug effects*,  physiology
Artemisinins / chemistry,  toxicity*
HeLa Cells
Heme / metabolism*
Humans
Iron / metabolism
Mitochondria / drug effects*,  metabolism
Peroxides / metabolism
Reactive Oxygen Species / metabolism
Grant Support
ID/Acronym/Agency:
G0700654//Medical Research Council; //Medical Research Council
Chemical
Reg. No./Substance:
0/Antimalarials; 0/Artemisinins; 0/Peroxides; 0/Reactive Oxygen Species; 42VZT0U6YR/Heme; 83507-69-1/artesunate; 9RMU91N5K2/artemisinine; E1UOL152H7/Iron
Comments/Corrections

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