{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T13:02:22Z","timestamp":1779714142822,"version":"3.53.1"},"reference-count":55,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science, Research and Innovation Fund","award":["B13F680065"],"award-info":[{"award-number":["B13F680065"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cancer remains a leading cause of mortality worldwide, largely due to dysregulated apoptotic signaling and the persistent activation of oncogenic pathways. However, natural products are a promising source of multi-target anticancer agents. In this study, we investigated the anticancer activity and underlying mechanisms of Clausena harmandiana root extract and its major carbazole alkaloid, 7-methoxyheptaphylline, both in vitro and in vivo. High-Performance Liquid Chromatography (HPLC) chemical fingerprinting confirmed the presence of bioactive coumarins and carbazole alkaloids in the extract. Cytotoxicity assays demonstrated that the extract significantly reduced the viability of human colorectal adenocarcinoma (HT-29), human hepatocellular carcinoma (HepG2), human lung adenocarcinoma (A549\u2013Luc2), and murine Lewis lung carcinoma (3LL\u2013Luc2) cells in a dose- and time-dependent manner. Our mechanistic investigations revealed the activation of JNK signaling, downregulation of anti-apoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1), and increased cleaved caspase-3 expression, indicating that mitochondrial apoptosis was induced. Notably, 7-methoxyheptaphylline markedly suppressed STAT3 phosphorylation in a concentration-dependent manner, comparable to the STAT3 inhibitor JSI-124. In a syngeneic 3LL\u2013Luciferase2 lung cancer mouse model, oral administration of C. harmandiana capsules significantly reduced tumor growth and bioluminescence intensity compared with controls. These in vivo findings were consistent with the inhibition of STAT3 signaling and induction of apoptosis observed in vitro. Collectively, our results demonstrate that C. harmandiana exerts broad-spectrum anticancer activity through coordinated modulation of the JNK\u2013STAT3 axis, leading to caspase-dependent apoptosis. These findings highlight its potential as a promising candidate for the development of STAT3-targeted anticancer therapies.<\/jats:p>","DOI":"10.3390\/ijms27114743","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T11:57:44Z","timestamp":1779710264000},"page":"4743","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anticancer Effects of Clausena hamandiana: Ethanolic Extract Inhibits Cancer Cell Proliferation and Suppresses Lung Tumorigenesis in Mice"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4065-6090","authenticated-orcid":false,"given":"Chantana","family":"Boonyarat","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7921-1171","authenticated-orcid":false,"given":"Yoshihiro","family":"Hayakawa","sequence":"additional","affiliation":[{"name":"Institute of Natural Medicine, University of Toyama, Toyama-shi 930-0194, Toyama, Japan"},{"name":"Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nutjakorn","family":"Samar","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nawinda","family":"Vanichakulthada","sequence":"additional","affiliation":[{"name":"College of Medicine and Public Health, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rawiwun","family":"Kaewamatawong","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6887-8181","authenticated-orcid":false,"given":"Teeraporn Sadira","family":"Supapaan","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjabhorn","family":"Sethabouppha","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9114-1698","authenticated-orcid":false,"given":"Pornthip","family":"Waiwut","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1126\/science.1235122","article-title":"Cancer genome landscapes","volume":"339","author":"Vogelstein","year":"2013","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/35077213","article-title":"Proliferation, cell cycle and apoptosis in cancer","volume":"411","author":"Evan","year":"2001","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.cell.2006.11.001","article-title":"Cancer metastasis: Building a framework","volume":"127","author":"Gupta","year":"2006","journal-title":"Cell"},{"key":"ref_5","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. 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