{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T01:42:28Z","timestamp":1777167748772,"version":"3.51.4"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Acute myeloid leukemia (AML) is an aggressive hematological malignancy with limited therapeutic options. Despite recent advances in targeted therapies, patients are still faced with poor survival outcomes. Thus, development of novel therapeutic agents with broad efficacy remains an urgent need.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a natural compound library screen and identified 6-methoxydihydroavicine, a plant-derived benzophenanthridine alkaloid (BPA) derived from the genus of <jats:italic>Macleaya<\/jats:italic> - a perennial herb found in China, North America and Europe - as a potent compound that reduced AML cell viability. We evaluated its cytotoxicity in multiple AML cell lines and investigated its underlying mechanism of action using assays that probed mitochondrial function, and reactive oxygen species (ROS) production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>6-methoxydihydroavicine significantly reduced cell viability and induced caspase-mediated cell death in AML cell lines in a dose-dependent manner. Mechanistically, 6-methoxydihydroavicine triggered accumulation of mitochondrial ROS and disrupted electron transport chain (ETC) function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings demonstrate that 6-methoxydihydroavicine exerts strong cytotoxic effects against AML cells through mitochondrial dysfunction and ROS-mediated apoptosis. As a natural, plant-derived compound with distinct anti-AML properties, 6-methoxydihydroavicine represents a promising candidate for further development as a therapeutic agent for AML.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1621050","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T05:20:55Z","timestamp":1750742455000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["6-Methoxydihydroavicine is a benzophenanthridine alkaloid with anti-leukemia activity"],"prefix":"10.3389","volume":"16","author":[{"given":"Yingying","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul A.","family":"Spagnuolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.3390\/biomedicines10081795","article-title":"Sanguinarine induces H2O2-dependent apoptosis and ferroptosis in human cervical cancer","volume":"10","author":"Alakkal","year":"2022","journal-title":"Biomedicines"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e2716","DOI":"10.1038\/cddis.2017.133","article-title":"Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells","volume":"8","author":"Basit","year":"2017","journal-title":"Cell Death Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"4660","DOI":"10.1002\/ptr.7099","article-title":"Natural products: a lead for drug discovery and development","volume":"35","author":"Chopra","year":"2021","journal-title":"Phytother. 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