{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:41:40Z","timestamp":1792737700443,"version":"4.5.0"},"reference-count":49,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2027,1,1]],"date-time":"2027-01-01T00:00:00Z","timestamp":1798761600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2027,1,1]],"date-time":"2027-01-01T00:00:00Z","timestamp":1798761600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2027,1,1]],"date-time":"2027-01-01T00:00:00Z","timestamp":1798761600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2027,1,1]],"date-time":"2027-01-01T00:00:00Z","timestamp":1798761600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2027,1,1]],"date-time":"2027-01-01T00:00:00Z","timestamp":1798761600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2027,1,1]],"date-time":"2027-01-01T00:00:00Z","timestamp":1798761600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2027,1,1]],"date-time":"2027-01-01T00:00:00Z","timestamp":1798761600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100010804","name":"Faculty of Medicine, Prince of Songkla University","doi-asserted-by":"publisher","award":["2-19 \/2567"],"award-info":[{"award-number":["2-19 \/2567"]}],"id":[{"id":"10.13039\/501100010804","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017170","name":"Thailand Science Research and Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017170","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005790","name":"Thammasat University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005790","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Ethnopharmacology"],"published-print":{"date-parts":[[2027,1]]},"DOI":"10.1016\/j.jep.2026.122274","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T16:27:10Z","timestamp":1786033630000},"page":"122274","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"special_numbering":"C","title":["Calotropis gigantea (L.) Dryand. Stem bark extract suppresses tumor angiogenesis through modulation of HIF-1\u03b1\/VEGF signaling and ERK1\/2-AKT activation in HepG2 xenograft-bearing nude mice"],"prefix":"10.1016","volume":"373","author":[{"given":"Aylada","family":"Kaenu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pholawat","family":"Tingpej","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phornphan","family":"Sornchuer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pritsana","family":"Piyabhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umarat","family":"Srisawat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naphatsanan","family":"Duansak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nattapon","family":"Sookprasert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2077-5888","authenticated-orcid":false,"given":"Supawadee","family":"Parhira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7023-3561","authenticated-orcid":false,"given":"Bhornprom","family":"Yoysungnoen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"2","key":"10.1016\/j.jep.2026.122274_bib1","article-title":"Matrix metalloproteinases in glioma: drivers of invasion and therapeutic targets","volume":"14","author":"Aitchison","year":"2025","journal-title":"BioTech (Basel)"},{"key":"10.1016\/j.jep.2026.122274_bib2","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2021.701369","article-title":"Evaluation of the Phytochemical, Antioxidant, Enzyme Inhibition, and Wound Healing Potential of Calotropis gigantea (L.) Dryand: A Source of a Bioactive Medicinal Product [Original Research]","volume":"12","author":"Alafnan","year":"2021","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.jep.2026.122274_bib3","article-title":"Akondo, Crown flower, Calotropis gigantea","author":"Ali","year":"2016","journal-title":"Flora of Banggladesh"},{"issue":"10","key":"10.1016\/j.jep.2026.122274_bib4","article-title":"Hypoxia-Inducible factor 1-Alpha (HIF-1\u03b1) and cancer: mechanisms of tumor hypoxia and therapeutic targeting","volume":"16","author":"Basheeruddin","year":"2024","journal-title":"Cureus"},{"issue":"7070","key":"10.1016\/j.jep.2026.122274_bib5","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/nature04478","article-title":"Angiogenesis in life, disease and medicine","volume":"438","author":"Carmeliet","year":"2005","journal-title":"Nature"},{"issue":"6","key":"10.1016\/j.jep.2026.122274_bib6","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nm0603-669","article-title":"The biology of VEGF and its receptors","volume":"9","author":"Ferrara","year":"2003","journal-title":"Nat. Med."},{"key":"10.1016\/j.jep.2026.122274_bib7","first-page":"15","article-title":"Notes on herbal recipes of Bodo tribe in Kamrup District, Assam","volume":"13","author":"Gogoi","year":"2001","journal-title":"Ethnobotany"},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib8","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/s41598-020-79547-w","article-title":"Compositions and antimicrobial properties of binary ZnO-CuO nanocomposites encapsulated calcium and carbon from Calotropis gigantea targeted for skin pathogens","volume":"11","author":"Govindasamy","year":"2021","journal-title":"Sci. Rep."},{"key":"10.1016\/j.jep.2026.122274_bib9","article-title":"Calotropis gigantea (Linnaeus) W. T. Aiton, Hortus Kew","volume":"16","author":"Gua","year":"1995","journal-title":"Flora of China"},{"key":"10.1016\/j.jep.2026.122274_bib10","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jare.2020.11.003","article-title":"33-kDa ANXA3 isoform contributes to hepatocarcinogenesis via modulating ERK, PI3K\/Akt-HIF and intrinsic apoptosis pathways","volume":"30","author":"Guo","year":"2021","journal-title":"J. Adv. Res."},{"key":"10.1016\/j.jep.2026.122274_bib11","doi-asserted-by":"crossref","DOI":"10.1016\/j.jep.2024.118516","article-title":"The dichloromethane fraction from Calotropis gigantea (L.) dryand. stem bark extract prevents liver cancer in SDT rats with insulin-independent diabetes mellitus","volume":"334","author":"Haewphet","year":"2024","journal-title":"J. Ethnopharmacol."},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib12","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/nrc704","article-title":"Hypoxia-a key regulatory factor in tumour growth","volume":"2","author":"Harris","year":"2002","journal-title":"Nat. Rev. Cancer"},{"issue":"5","key":"10.1016\/j.jep.2026.122274_bib13","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.ceb.2010.07.006","article-title":"VE-cadherin: at the front, center, and sides of endothelial cell organization and function","volume":"22","author":"Harris","year":"2010","journal-title":"Curr. Opin. Cell Biol."},{"key":"10.1016\/j.jep.2026.122274_bib14","doi-asserted-by":"crossref","DOI":"10.1016\/j.phytochem.2021.112951","article-title":"Cytotoxic cardenolides from Calotropis gigantea","volume":"192","author":"He","year":"2021","journal-title":"Phytochemistry"},{"issue":"2","key":"10.1016\/j.jep.2026.122274_bib15","doi-asserted-by":"crossref","DOI":"10.1002\/cai2.70059","article-title":"Global advances in hepatocellular carcinoma research and therapy in 2025","volume":"5","author":"Hu","year":"2026","journal-title":"Cancer Innov"},{"issue":"3","key":"10.1016\/j.jep.2026.122274_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.heliyon.2025.e41963","article-title":"HPLC-MS standardization and validation methods for determination of calactin content in dichloromethane fraction of Calotropis gigantea (L.) Dryand. (Niu jiao gua) stem bark and its application in prediction of anticancer activities","volume":"11","author":"Kaewpaeng","year":"2025","journal-title":"Heliyon"},{"issue":"16","key":"10.1016\/j.jep.2026.122274_bib17","doi-asserted-by":"crossref","DOI":"10.3390\/molecules27165310","article-title":"Green synthesis and antimicrobial activities of silver nanoparticles using Calotropis gigantea from Ie Seu-Um geothermal area, Aceh Province, Indonesia","volume":"27","author":"Kemala","year":"2022","journal-title":"Molecules"},{"key":"10.1016\/j.jep.2026.122274_bib18","first-page":"1607","article-title":"Calotropis gigantea","volume":"3","author":"Kirtikar","year":"1980","journal-title":"Indian medicinal plants"},{"issue":"5","key":"10.1016\/j.jep.2026.122274_bib19","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1097\/CEJ.0b013e3283498e66","article-title":"The small molecule calactin induces DNA damage and apoptosis in human leukemia cells","volume":"21","author":"Lee","year":"2012","journal-title":"Eur. J. Cancer Prev."},{"issue":"8","key":"10.1016\/j.jep.2026.122274_bib20","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1021\/np060249f","article-title":"19-Nor- and 18,20-Epoxy-cardenolides from the leaves of Calotropis gigantea","volume":"69","author":"Lhinhatrakool","year":"2006","journal-title":"J. Nat. Prod."},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib21","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/s41392-023-01460-1","article-title":"Angiogenic signaling pathways and anti-angiogenic therapy for cancer","volume":"8","author":"Liu","year":"2023","journal-title":"Signal Transduct. Targeted Ther."},{"issue":"5","key":"10.1016\/j.jep.2026.122274_bib22","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.apsb.2015.05.007","article-title":"HIF-1\u03b1 pathway: role, regulation and intervention for cancer therapy","volume":"5","author":"Masoud","year":"2015","journal-title":"Acta Pharm. Sin. B"},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib23","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.advenzreg.2006.01.004","article-title":"Roles of the RAF\/MEK\/ERK and PI3K\/PTEN\/AKT pathways in malignant transformation and drug resistance","volume":"46","author":"McCubrey","year":"2006","journal-title":"Adv. Enzym. Regul."},{"issue":"8","key":"10.1016\/j.jep.2026.122274_bib24","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0104544","article-title":"In vitro anti-influenza virus activities of a new lignan glycoside from the latex of Calotropis gigantea","volume":"9","author":"Parhira","year":"2014","journal-title":"PLoS One"},{"key":"10.1016\/j.jep.2026.122274_bib25","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.jep.2016.10.070","article-title":"Cardenolides from Calotropis gigantea as potent inhibitors of hypoxia-inducible factor-1 transcriptional activity","volume":"194","author":"Parhira","year":"2016","journal-title":"J. Ethnopharmacol."},{"issue":"4748","key":"10.1016\/j.jep.2026.122274_bib26","first-page":"1","article-title":"2'-Epi-uscharin from the latex of Calotropis gigantea with HIF-1 inhibitory activity","volume":"4","author":"Parhira","year":"2014","journal-title":"Sci. Rep."},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib27","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-022-16321-0","article-title":"Calotropis gigantea stem bark extracts inhibit liver cancer induced by diethylnitrosamine","volume":"12","author":"Sawong","year":"2022","journal-title":"Sci. Rep."},{"issue":"10","key":"10.1016\/j.jep.2026.122274_bib28","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/nrc1187","article-title":"Targeting HIF-1 for cancer therapy","volume":"3","author":"Semenza","year":"2003","journal-title":"Nat. Rev. Cancer"},{"issue":"11","key":"10.1016\/j.jep.2026.122274_bib29","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1016\/j.bcp.2013.03.006","article-title":"Ursolic acid in cancer prevention and treatment: molecular targets, pharmacokinetics and clinical studies","volume":"85","author":"Shanmugam","year":"2013","journal-title":"Biochem. Pharmacol."},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib30","first-page":"114","article-title":"ERK and Akt exhibit distinct signaling responses following stimulation by pro-angiogenic factors","volume":"18","author":"Song","year":"2020","journal-title":"Cell. Signal."},{"issue":"5","key":"10.1016\/j.jep.2026.122274_bib31","doi-asserted-by":"crossref","DOI":"10.1016\/j.heliyon.2023.e16375","article-title":"Calotropis gigantea stem bark extract activates HepG2 cell apoptosis through ROS and its effect on cytochrome P450","volume":"9","author":"Suknoppakit","year":"2023","journal-title":"Heliyon"},{"issue":"3","key":"10.1016\/j.jep.2026.122274_bib32","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"10.1016\/j.jep.2026.122274_bib33","series-title":"Thailand Guideline for Management of Hepatocellular Carcinoma 2021","article-title":"The committee for the development of the guideline for liver cancer management in Thailand","year":"2021"},{"issue":"2","key":"10.1016\/j.jep.2026.122274_bib34","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1161\/ATVBAHA.107.158014","article-title":"VE-cadherin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation","volume":"28","author":"Vestweber","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"issue":"7","key":"10.1016\/j.jep.2026.122274_bib35","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nrc839","article-title":"The phosphatidylinositol 3-Kinase AKT pathway in human cancer","volume":"2","author":"Vivanco","year":"2002","journal-title":"Nat. Rev. Cancer"},{"issue":"2","key":"10.1016\/j.jep.2026.122274_bib36","doi-asserted-by":"crossref","first-page":"755","DOI":"10.3892\/or.2017.5719","article-title":"P18 peptide, a functional fragment of pigment epithelial-derived factor, inhibits angiogenesis in hepatocellular carcinoma via modulating VEGF\/VEGFR2 signalling pathway","volume":"38","author":"Wang","year":"2017","journal-title":"Oncol. Rep."},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib37","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1186\/s12885-016-2767-2","article-title":"Bicyclol induces cell cycle arrest and autophagy in HepG2 human hepatocellular carcinoma cells through the PI3K\/AKT and Ras\/Raf\/MEK\/ERK pathways","volume":"16","author":"Wang","year":"2016","journal-title":"BMC Cancer"},{"issue":"12","key":"10.1016\/j.jep.2026.122274_bib38","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.3390\/molecules13123033","article-title":"A new cytotoxic pregnanone from Calotropis gigantea","volume":"13","author":"Wang","year":"2008","journal-title":"Molecules"},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1056\/NEJM199101033240101","article-title":"Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma","volume":"324","author":"Weidner","year":"1991","journal-title":"N. Engl. J. Med."},{"issue":"8","key":"10.1016\/j.jep.2026.122274_bib40","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0254392","article-title":"Calotropis gigantea stem bark extract induced apoptosis related to ROS and ATP production in colon cancer cells","volume":"16","author":"Winitchaikul","year":"2021","journal-title":"PLoS One"},{"key":"10.1016\/j.jep.2026.122274_bib41","doi-asserted-by":"crossref","DOI":"10.1159\/000550954","article-title":"Survival outcomes, recurrence patterns, and its corresponding therapeutic management after conversion therapy followed by curative resection for hepatocellular carcinoma: a real-world study","author":"Xiao","year":"2026","journal-title":"Liver Cancer"},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib42","doi-asserted-by":"crossref","first-page":"25","DOI":"10.20892\/j.issn.2095-3941.2022.0449","article-title":"Angiogenesis in hepatocellular carcinoma: mechanisms and anti-angiogenic therapies","volume":"20","author":"Yao","year":"2023","journal-title":"Cancer Biol. Med."},{"issue":"10","key":"10.1016\/j.jep.2026.122274_bib43","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.steroids.2013.06.002","article-title":"Cytotoxic cardenolides from the root bark of Calotropis gigantea","volume":"78","author":"You","year":"2013","journal-title":"Steroids"},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib44","doi-asserted-by":"crossref","DOI":"10.3892\/or.2023.8573","article-title":"Saikosaponin b2 inhibits tumor angiogenesis in liver cancer via down-regulation of VEGF\/ERK\/HIF-1\u03b1 signaling","volume":"50","author":"You","year":"2023","journal-title":"Oncol. Rep."},{"key":"10.1016\/j.jep.2026.122274_bib45","doi-asserted-by":"crossref","DOI":"10.3389\/fnut.2023.1221935","article-title":"Short term effect of tetrahydrocurcumin on adipose angiogenesis in very high-fat diet-induced obesity mouse model","volume":"10","author":"Yoysungnoen","year":"2023","journal-title":"Front. Nutr."},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib46","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s12672-025-02198-8","article-title":"Advancements and limitations in traditional anti-cancer therapies: a comprehensive review of surgery, chemotherapy, radiation therapy, and hormonal therapy","volume":"16","author":"Zafar","year":"2025","journal-title":"Discov. Oncol."},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib47","article-title":"Hormetic effect of panaxatriol saponins confers neuroprotection in PC12 cells and zebrafish through PI3K\/AKT\/mTOR and AMPK\/SIRT1\/FOXO3 pathways","volume":"7","author":"Zhang","year":"2017","journal-title":"Sci. Rep."},{"issue":"1","key":"10.1016\/j.jep.2026.122274_bib48","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41392-024-02075-w","article-title":"Hepatocellular carcinoma: signaling pathways and therapeutic advances","volume":"10","author":"Zheng","year":"2025","journal-title":"Signal Transduct. Targeted Ther."},{"key":"10.1016\/j.jep.2026.122274_bib49","doi-asserted-by":"crossref","DOI":"10.1016\/j.bioorg.2021.104740","article-title":"Non-classical cardenolides from Calotropis gigantea exhibit anticancer effect as HIF-1 inhibitors","volume":"109","author":"Zheng","year":"2021","journal-title":"Bioorg. Chem."}],"container-title":["Journal of Ethnopharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0378874126011293?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0378874126011293?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:36:32Z","timestamp":1792737392000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0378874126011293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2027,1]]},"references-count":49,"alternative-id":["S0378874126011293"],"URL":"https:\/\/doi.org\/10.1016\/j.jep.2026.122274","relation":{},"ISSN":["0378-8741"],"issn-type":[{"value":"0378-8741","type":"print"}],"subject":[],"published":{"date-parts":[[2027,1]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Calotropis gigantea (L.) Dryand. Stem bark extract suppresses tumor angiogenesis through modulation of HIF-1\u03b1\/VEGF signaling and ERK1\/2-AKT activation in HepG2 xenograft-bearing nude mice","name":"articletitle","label":"Article Title"},{"value":"Journal of Ethnopharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jep.2026.122274","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"122274"}}