{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T12:33:17Z","timestamp":1787142797683,"version":"build-2736575974"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"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. Oncol."],"abstract":"<jats:p>\n                    Amentoflavone (AF) is a naturally occurring biflavonoid isolated from multiple medicinal plants and widely studied for anti-inflammatory and antioxidant activities. In oncology, AF has emerged as a pleiotropic small molecule that modulates interconnected signaling axes rather than a single node. Preclinical studies indicate that AF attenuates PI3K\/Akt\/mTOR signaling and NF-\u03baB\u2013dependent survival programs, disrupts Wnt\/\u03b2-catenin\u2013linked epithelial\u2013mesenchymal transition (EMT), and modulates MAPK cascades to promote apoptosis and cell-cycle arrest. AF also interferes with pro-angiogenic signaling and VEGF-driven neovascularization. Across diverse cancer models, these activities translate into reduced proliferation, enhanced apoptosis, suppression of invasion\/EMT, and inhibition of tumor-associated angiogenesis. However, translation remains limited by poor aqueous solubility, low oral exposure, and incomplete exposure\u2013response and safety characterization. Recent drug delivery approaches (polymeric micelles, mixed nanomicelles, DSPE-PEG micelles) and rational combination strategies provide practical routes to improve systemic exposure and revisit AF in combination regimens. This review integrates mechanistic and tumor-specific evidence with a clear distinction between direct target binding and downstream pathway readouts, quantitative\n                    <jats:italic>in vitro<\/jats:italic>\n                    \/\n                    <jats:italic>in vivo<\/jats:italic>\n                    endpoints, an expanded reference list using verifiable sources, and priorities for pharmacokinetic optimization, toxicity evaluation, and biomarker-guided early-phase development.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1813172","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:11:57Z","timestamp":1785427917000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Amentoflavone and cancer: mechanistic insights and translational perspectives"],"prefix":"10.3389","volume":"16","author":[{"given":"Hiroki","family":"Hashida","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery, Hanwa Memorial Hospital","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Hanwa Memorial Hospital","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatoshi","family":"Akagami","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Hanwa Memorial Hospital","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Hanwa Memorial Hospital","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Hanwa Memorial Hospital","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural products as sources of new drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J Nat Prod"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/ph16091229","article-title":"Anticancer potential of flavonoids: An overview","volume":"16","author":"de Luna","year":"2023","journal-title":"Pharm (Basel)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/molecules22020299","article-title":"A review on the phytochemistry, pharmacology, and pharmacokinetics of amentoflavone, a naturally-occurring biflavonoid","volume":"22","author":"Yu","year":"2017","journal-title":"Molecules"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.768708","article-title":"Insights into amentoflavone: A natural multifunctional biflavonoid","volume":"12","author":"Xiong","year":"2021","journal-title":"Front Pharmacol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"6088","DOI":"10.3390\/molecules26196088","article-title":"Proceedings of chemistry, pharmacology, and pharmacokinetics of amentoflavone","volume":"26","author":"He","year":"2021","journal-title":"Molecules"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.186239","article-title":"The biflavonoid amentoflavone inhibits neovascularization preventing the activity of proangiogenic vascular endothelial growth factors","volume":"286","author":"Tarallo","year":"2011","journal-title":"J Biol Chem"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1021\/jf5019615","article-title":"Liquid chromatography\u2013tandem mass spectrometry method and pharmacokinetic behavior following administration by different routes and bioavailability of amentoflavone in rats","author":"Liao","year":"2015","journal-title":"J Agric Food Chem"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/chromsci\/bmy066","article-title":"Simultaneous determination of quercitrin, afzelin, amentoflavone and hinokiflavone after oral administration of P. orientalis extract: pharmacokinetic application","volume":"56","author":"Shan","year":"2018","journal-title":"J Chromatogr Sci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.2304","article-title":"Evaluation on absorption risks of amentoflavone after oral administration (in vitro\/in silico assessment)","volume":"42","author":"Qiu","year":"2021","journal-title":"Biopharm Drug Dispos"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.9b03275","article-title":"Facile fabrication of an amentoflavone-loaded micelle system for oral delivery to improve bioavailability","volume":"11","author":"Zhang","year":"2019","journal-title":"ACS Appl Mater Interfaces"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/10717544.2019.1709920","article-title":"Preparation, evaluation and metabolites study in rats of novel amentoflavone-loaded TPGS\/soluplus mixed nanomicelles","author":"Feng","year":"2020","journal-title":"Drug Delivery"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.5690","article-title":"Preparation of amentoflavone-loaded DSPE-PEG2000 micelles with improved bioavailability and in vitro antitumor efficacy","author":"Feng","year":"2023","journal-title":"BioMed Chromatogr"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1134\/s0006297908020132","article-title":"Inhibition of tumor specific angiogenesis by amentoflavone","author":"Guruvayoorappan","year":"2008","journal-title":"BioMed Pharmacother"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1023\/A:1019963222510","article-title":"Inhibition of TNF\u03b1-induced cyclooxygenase-2 expression by amentoflavone","author":"Banerjee","year":"2002","journal-title":"Mol Cell Biochem"},{"key":"B15","doi-asserted-by":"crossref","DOI":"10.2147\/JIR.S521756","article-title":"Amentoflavone impedes NF-\u03baB activation and mediates apoptosis induction in lung cancer A549 cells (in vitro\/in silico)","author":"Faiyaz","year":"2025","journal-title":"J Inflammation Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s13167-021-00242-5","article-title":"Flavonoids as an effective sensitizer for anti-cancer therapy","author":"Liskova","year":"2021","journal-title":"Biophys Rev"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.21037\/atm-22-3035","article-title":"Amentoflavone inhibits colorectal cancer EMT via the miR-16-5p\/HMGA2\/\u03b2-catenin pathway","volume":"10","author":"Cai","year":"2022","journal-title":"Ann Transl Med"},{"key":"B18","article-title":"5-Fluorouracil (5-FU) resistance and strategies to increase sensitivity in colorectal cancer: Mechanisms and approaches","author":"Sethy","year":"2021","journal-title":"Life Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s12010-011-9500-z","article-title":"Amentoflavone inhibits UVB-induced matrix metalloproteinase-1 expression through modulation of AP-1 components in normal human fibroblasts","author":"Lee","year":"2012","journal-title":"Appl Biochem Biotechnol"},{"key":"B20","article-title":"Amentoflavone induces anti-angiogenic and anti-metastatic effects through suppression of NF-\u03baB activation in MCF-7 cells","author":"Chen","year":"2015","journal-title":"Anticancer Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2017.6540","article-title":"Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant HCC cells","author":"Chen","year":"2017","journal-title":"Oncol Lett"},{"key":"B22","article-title":"Amentoflavone enhances the therapeutic efficacy of sorafenib by inhibiting anti-apoptotic potential and potentiating apoptosis in HCC in vivo","author":"Tsai","year":"2018","journal-title":"Anticancer Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.21873\/invivo.11274","article-title":"Amentoflavone inhibits ERK-modulated tumor progression in hepatocellular carcinoma in vitro","volume":"32","author":"Lee","year":"2018","journal-title":"In Vivo"},{"key":"B24","article-title":"Amentoflavone induces cell-cycle arrest and apoptosis in MCF-7 human breast cancer cells","author":"Pei","year":"2012","journal-title":"Anticancer Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1089\/jmf.2010.1428","article-title":"The biflavonoid amentoflavone induces apoptosis in human cervical cancer cells via blocking E7-mediated COX-2\/IL-32 activation","author":"Lee","year":"2011","journal-title":"J Med Food"},{"key":"B26","first-page":"4911","article-title":"Amentoflavone inhibits metastatic potential through suppression of ERK and NF-\u03baB activation in osteosarcoma cells","volume":"37","author":"Pan","year":"2017","journal-title":"Anticancer Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.21873\/invivo.12812","article-title":"Reinforcement of sorafenib anti-osteosarcoma effect by amentoflavone is associated with induction of apoptosis and inactivation of ERK\/NF-\u03baB","author":"Su","year":"2022","journal-title":"In Vivo"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20030642","article-title":"Cyclodextrin\u2013drug inclusion complexes: In vivo and in vitro approaches","volume":"20","author":"Carneiro","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.0c04532","article-title":"Systematic strategy for metabolites of amentoflavone in vivo and in vitro based on UHPLC-Q-TOF-MS\/MS analysis","author":"Wang","year":"2020","journal-title":"J Agric Food Chem"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2009.10.041","article-title":"Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity","volume":"48","author":"Kimura","year":"2010","journal-title":"Food Chem Toxicol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1108867","article-title":"Inhibitory effect of Selaginella doederleinii hieron on human cytochrome P450","volume":"14","author":"Lin","year":"2023","journal-title":"Front Pharmacol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"7731","DOI":"10.3390\/ijms24097731","article-title":"Advances in the anti-tumor activity of biflavonoids: Targeting signaling and microenvironmental nodes","volume":"24","author":"Ren","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B33","unstructured":"U.S. National Library of Medicine (NIH)"},{"key":"B34","unstructured":"International Clinical Trials Registry Platform (Ictrp)"},{"key":"B35","unstructured":"Botanical drug development: guidance for industry. Revision 1\n          \n          \n          \n          2016"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.9b00949","article-title":"Scientific and regulatory approach to botanical drug development: A U.S. FDA perspective","volume":"83","author":"Wu","year":"2020","journal-title":"J Nat Prod"}],"updated-by":[{"DOI":"10.3389\/fonc.2026.1955891","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000}}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1813172\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T12:17:03Z","timestamp":1787141823000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1813172\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":36,"alternative-id":["10.3389\/fonc.2026.1813172"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1813172","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]},"article-number":"1813172"}}