The Role of Heme and the Mitochondrion in the Chemical and Molecular Mechanisms of Mammalian Cell Death Induced by the Artemisinin Antimalarials
HeLa
Dihydroartemisinin
DOI:
10.1074/jbc.m110.144188
Publication Date:
2010-11-09T05:39:10Z
AUTHORS (5)
ABSTRACT
The artemisinin compounds are the frontline drugs for treatment of drug-resistant malaria. They selectively cytotoxic to mammalian cancer cell lines and have been implicated as neurotoxic embryotoxic in animal studies. endoperoxide functional group is both pharmacophore toxicophore, but proposed chemical mechanisms targets cytotoxicity remain unclear. In this study we used models quantitative drug metabolite analysis define role mitochondrion cellular heme molecular death induced by compounds. HeLa ρ(0) cells, which devoid a functioning electron transport chain, were demonstrate that actively respiring mitochondria play an essential endoperoxide-induced (artesunate IC(50) values, 48 h: 6 ± 3 μM; 34 5 μM) via generation reactive oxygen species induction mitochondrial dysfunction apoptosis do not any reductive activation carbon-centered radicals. However, using modulators synthesis (succinylacetone protoporphyrin IX) iron content (holotransferrin), demonstrated definitively free or protein-bound responsible intracellular basis (IC(50) value biomarker bioactivation levels, respectively: 10β-(p-fluorophenoxy)dihydroartemisinin alone, 0.36 0.20 μM 11 5%; with succinylacetone, >100 2 5%).
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