The Role of Heme and the Mitochondrion in the Chemical and Molecular Mechanisms of Mammalian Cell Death Induced by the Artemisinin Antimalarials
| Autor: | Amy E. Mercer, Paul M. O'Neill, James L. Maggs, B. Kevin Park, Ian M. Copple |
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| Rok vydání: | 2011 |
| Předmět: |
Iron
medicine.medical_treatment Artesunate Dihydroartemisinin Apoptosis Heme Mitochondrion Biology Biochemistry HeLa Antimalarials 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Humans Cytotoxicity Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences Reactive oxygen species Cell Biology biology.organism_classification Artemisinins Mitochondria Peroxides 3. Good health Metabolism chemistry 030220 oncology & carcinogenesis Reactive Oxygen Species Intracellular HeLa Cells |
| Zdroj: | Journal of Biological Chemistry; Vol 286 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m110.144188 |
| Popis: | 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%). |
| Databáze: | OpenAIRE |
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