ArticleThe Journal of biological chemistry2011
The role of heme and the mitochondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarials.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 165 citations in OpenAlex.
- Overcoming venetoclax resistance through heme-mediated NOXA/cyclin D1/Mcl-1 axis with a novel artemisinin conjugate.Blood advances · 2025Article
- Antitumour effects of artesunate via cell cycle checkpoint controls in human oesophageal squamous carcinoma cells.European journal of medical research · 2024Article
- Zinc Protoporphyrin-9 Potentiates the Anticancer Activity of Dihydroartemisinin.Antioxidants (Basel, Switzerland) · 2023Article
- The Role of Circadian Clock Genes in Critical Illness: The Potential Role of Translational Clock Gene Therapies for Targeting Inflammation, Mitochondrial Function, and Muscle Mass in Intensive Care.Journal of biological rhythms · 2022Review
- The Antagonizing Role of Heme in the Antimalarial Function of Artemisinin: Elevating Intracellular Free Heme Negatively Impacts Artemisinin Activity inMolecules (Basel, Switzerland) · 2022Article
- The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer.Oxidative medicine and cellular longevity · 2022Review
- Reactive Oxygen Species as the Brainbox in Malaria Treatment.Antioxidants (Basel, Switzerland) · 2021Review
- The Real Cytotoxic Effect of Artemisinins on Colon Cancer Cells in a Physiological Cell Culture Setting. How Composition of the Culture Medium Biases Experimental Findings.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Article
- The Anticancer Properties of Artemisia aucheri Boiss Extract on HT29 Colon Cancer Cells.Journal of gastrointestinal cancer · 2021Article
- Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclax.Blood advances · 2021Article
- Repositioning of Antiparasitic Drugs for Tumor Treatment.Frontiers in oncology · 2021Review
- Advances in the research on the targets of anti-malaria actions of artemisinin.Pharmacology & therapeutics · 2020Review
- Effects and Mechanism of Action of Artemisinin on Mitochondria of Plasmodium berghei.Chinese journal of integrative medicine · 2020Article
- Heme-Dependent ER Stress Apoptosis: A Mechanism for the Selective Toxicity of the Dihydroartemisinin, NSC735847, in Colorectal Cancer Cells.Frontiers in oncology · 2020Article
- Evolution of resistance in vitro reveals mechanisms of artemisinin activity inProceedings of the National Academy of Sciences of the United States of America · 2019Article
- Antimalarial Drugs Enhance the Cytotoxicity of 5-Aminolevulinic Acid-Based Photodynamic Therapy against the Mammary Tumor Cells of Mice In Vitro.Molecules (Basel, Switzerland) · 2019Article
- Exogenous Iron Increases Fasciocidal Activity and Hepatocellular Toxicity of the Synthetic Endoperoxides OZ78 and MT04.International journal of molecular sciences · 2019Article
- Synergistic antitumor activity of artesunate and HDAC inhibitors through elevating heme synthesisActa pharmaceutica Sinica. B · 2019Article
- Artemisinin and Its Synthetic Derivatives as a Possible Therapy for Cancer.Medical sciences (Basel, Switzerland) · 2018Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
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%).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.