Artesunate acts through cytochrome c to inhibit growth of pediatric AML cells

• Published in: Scientific reports Vol. 13; no. 1; p. 22383
• Main Authors: Hill, Kristen S., Schuler, Erin E., Ellingson, Sally R., Kolesar, Jill M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-12-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67; 631/67/1059; 631/67/1990; 631/67/1990/283; 631/67/1990/283/1897; 631/67/2332; 692/699/1541/1990; 692/699/67; Acute myeloid leukemia; Antimalarials - pharmacology; Antimalarials - therapeutic use; Antitumor activity; Apoptosis; Artemisia annua; Artemisinin; Artemisinins - pharmacology; Artesunate; Artesunate - pharmacology; Binding sites; Cancer; Cell cycle; Cell death; Child; Cytochrome; Cytochrome c; Cytochromes c; Hematology; Heme; Herbal medicine; Humanities and Social Sciences; Humans; Informatics; Kinases; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Malaria; Medical research; Membrane potential; Mitochondria; multidisciplinary; Pediatrics; Pharmacy; Protein structure; Proteins; Science; Science (multidisciplinary); Solid tumors; Spectroscopy; Spectrum analysis; Traditional Chinese medicine; Tumors; Vector-borne diseases
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-49928-y

Artesunate is a derivative of artemisinin, an active compound isolated from
Artemisia annua
which has been used in Traditional Chinese Medicine and to treat malaria worldwide. Artemisinin derivatives have exhibited anti-cancer activity against both solid tumors and leukemia. The direct target(s) of artesunate are controversial; although, heme-bound proteins in the mitochondria have been implicated. We utilized computational modeling to calculate the predicted binding score of artesunate with heme-bound mitochondrial proteins and identified cytochrome c as potential artesunate target. UV–visible spectroscopy showed changes in the absorbance spectrum, and thus protein structure, when cytochrome c was incubated with artesunate. Artesunate induces apoptosis, disrupts mitochondrial membrane potential, and is antagonized by methazolamide in pediatric AML cells indicating a probable mechanism of action involving cytochrome c. We utilized a multi-disciplinary approach to show that artesunate can interact with and is dependent on cytochrome c release to induce cell death in pediatric AML cell lines.