{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T20:21:48Z","timestamp":1757622108656,"version":"3.44.0"},"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2022-NR070862"],"award-info":[{"award-number":["RS-2022-NR070862"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2024-00336900"],"award-info":[{"award-number":["RS-2024-00336900"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2023-00246380"],"award-info":[{"award-number":["RS-2023-00246380"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths, remaining a significant challenge in terms of early detection, effective treatment, and improving patient survival rates. In this study, we investigated the anticancer mechanism of rubiarbonol B (Ru-B) and its derivative 3-<jats:italic>O<\/jats:italic>-acetylrubiarbonol B (ARu-B), a pentacyclic terpenoid in gefitinib (GEF)-sensitive and -resistant NSCLC HCC827 cells. Concentration- and time-dependent cytotoxicity was observed for both Ru-B and ARu-B. The <jats:italic>in vitro<\/jats:italic> kinase assay showed that ARu-B treatment inhibited epidermal growth factor receptor (EGFR), mesenchymal-epithelial transition (MET), and AKT1, and their phosphorylation in HCC827 cells. A molecular docking model suggested that ARu-B could interact with EGFR and MET in different ways, either by binding to the ATP pocket or the substrate pocket. ARu-B induced reactive oxygen species (ROS) generation and cell cycle arrest. The induction of apoptosis through caspase activation was confirmed by preventing cytotoxicity with Z-VAD-FMK pretreatment. Taken together, ARu-B inhibited the growth of both GEF-sensitive and GEF-resistant NSCLC cells by targeting EGFR, MET, and AKT and inducing ROS generation and caspase activation. Further studies on ARu-B can improve the treatment of chemotherapy-resistant NSCLC through the development of effective ARu-B-based anticancer agents.<\/jats:p>","DOI":"10.1371\/journal.pone.0329706","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T17:32:08Z","timestamp":1757352728000},"page":"e0329706","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["3-O-acetylrubiarbonol B preferentially targets EGFR and MET over rubiarbonol B to inhibit NSCLC cell growth"],"prefix":"10.1371","volume":"20","author":[{"given":"A-Young","family":"Nam","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang Hoon","family":"Joo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na Yeong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Goo","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0001-7043","authenticated-orcid":true,"given":"Jin Woo","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MinKyun","family":"Na","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4062-4016","authenticated-orcid":true,"given":"Jung-Hyun","family":"Shim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"issue":"3","key":"pone.0329706.ref001","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":"H Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"issue":"1","key":"pone.0329706.ref002","first-page":"7","article-title":"Cancer statistics, 2022","volume":"72","author":"RL Siegel","year":"2022","journal-title":"CA Cancer J Clin"},{"issue":"4","key":"pone.0329706.ref003","first-page":"388","article-title":"Molecular targets in non-small cell lung cancer","volume":"17","author":"R Griffin","year":"2017","journal-title":"Ochsner J"},{"issue":"1","key":"pone.0329706.ref004","doi-asserted-by":"crossref","first-page":"188645","DOI":"10.1016\/j.bbcan.2021.188645","article-title":"Challenge and countermeasures for EGFR targeted therapy in non-small cell lung cancer","volume":"1877","author":"X Tian","year":"2022","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"pone.0329706.ref005","doi-asserted-by":"crossref","first-page":"102664","DOI":"10.1016\/j.ctrv.2023.102664","article-title":"The role of anti-EGFR therapies in EGFR-TKI-resistant advanced non-small cell lung cancer","volume":"122","author":"F Ciardiello","year":"2024","journal-title":"Cancer Treat Rev"},{"issue":"10","key":"pone.0329706.ref006","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1111\/cas.12497","article-title":"Anti-tumor activity of WK88-1, a novel geldanamycin derivative, in gefitinib-resistant non-small cell lung cancers with Met amplification","volume":"105","author":"W-J Jang","year":"2014","journal-title":"Cancer Sci"},{"issue":"2","key":"pone.0329706.ref007","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s10637-020-01010-4","article-title":"A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer","volume":"39","author":"J-J Yang","year":"2021","journal-title":"Invest New Drugs"},{"issue":"0","key":"pone.0329706.ref008","article-title":"Broad targeting of resistance to apoptosis in cancer","author":"RM Mohammad","year":"2015","journal-title":"Semin Cancer Biol"},{"issue":"4","key":"pone.0329706.ref009","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1007\/s10565-022-09774-6","article-title":"Rubiarbonol B induces RIPK1-dependent necroptosis via NOX1-derived ROS production","volume":"39","author":"HS Byun","year":"2023","journal-title":"Cell Biol Toxicol"},{"key":"pone.0329706.ref010","first-page":"33","article-title":"Chapter 2-Highlights of pentacyclic triterpenoids in the cancer settings","volume-title":"Studies in Natural Products Chemistry","author":"JAR Salvador","year":"2014"},{"key":"pone.0329706.ref011","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.jep.2017.10.026","article-title":"NF-\u03baB and JNK mediated apoptosis and G0\/G1 arrest of HeLa cells induced by rubiarbonol G, an arborinane-type triterpenoid from Rubia yunnanensis","volume":"220","author":"G-Z Zeng","year":"2018","journal-title":"J Ethnopharmacol"},{"key":"pone.0329706.ref012","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1055\/a-0855-4051","article-title":"Four new cytotoxic arborinane-type triterpenes from the endolichenic fungus Myrothecium inundatum","volume":"85","author":"BB Basnet","year":"2019","journal-title":"Planta Med"},{"issue":"4","key":"pone.0329706.ref013","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1007\/s10565-022-09774-6","article-title":"Rubiarbonol B induces RIPK1-dependent necroptosis via NOX1-derived ROS production","volume":"39","author":"HS Byun","year":"2023","journal-title":"Cell Biol Toxicol"},{"issue":"10","key":"pone.0329706.ref014","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1021\/acs.jnatprod.6b00489","article-title":"Arborinane triterpenoids from rubia philippinensis inhibit proliferation and migration of vascular smooth muscle cells induced by the platelet-derived growth factor","volume":"79","author":"KT Quan","year":"2016","journal-title":"J Nat Prod"},{"issue":"5827","key":"pone.0329706.ref015","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1126\/science.1141478","article-title":"MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling","volume":"316","author":"JA Engelman","year":"2007","journal-title":"Science"},{"issue":"6","key":"pone.0329706.ref016","doi-asserted-by":"crossref","first-page":"661","DOI":"10.4062\/biomolther.2023.155","article-title":"Licochalcone H targets EGFR and AKT to suppress the growth of oxaliplatin-sensitive and-resistant colorectal cancer cells","volume":"31","author":"SO Lee","year":"2023","journal-title":"Biomol Ther"},{"issue":"4","key":"pone.0329706.ref017","doi-asserted-by":"crossref","first-page":"446","DOI":"10.4062\/biomolther.2023.070","article-title":"3-Deoxysappanchalcone inhibits cell growth of gefitinib-resistant lung cancer cells by simultaneous targeting of EGFR and MET Kinases","volume":"31","author":"J-Y Lee","year":"2023","journal-title":"Biomol Ther (Seoul)"},{"issue":"2","key":"pone.0329706.ref018","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"O Trott","year":"2010","journal-title":"J Comput Chem"},{"issue":"6","key":"pone.0329706.ref019","doi-asserted-by":"crossref","first-page":"658","DOI":"10.4062\/biomolther.2021.143","article-title":"Podophyllotoxin Induces ROS-Mediated Apoptosis and Cell Cycle Arrest in Human Colorectal Cancer Cells via p38 MAPK Signaling","volume":"29","author":"S-O Lee","year":"2021","journal-title":"Biomol Ther (Seoul)"},{"issue":"9","key":"pone.0329706.ref020","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1007\/s11033-016-4032-9","article-title":"Triterpenes in cancer: significance and their influence","volume":"43","author":"BS Gill","year":"2016","journal-title":"Mol Biol Rep"},{"key":"pone.0329706.ref021","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1007\/s12272-024-01510-4","article-title":"Pentacyclic triterpenes, potential novel therapeutic approaches for cardiovascular diseases","volume":"47","author":"D Peng","year":"2024","journal-title":"Arch Pharm Res"},{"key":"pone.0329706.ref022","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.phymed.2018.09.011","article-title":"Pentacyclic triterpenes: New tools to fight metabolic syndrome","volume":"50","author":"H Sharma","year":"2018","journal-title":"Phytomedicine"},{"issue":"10","key":"pone.0329706.ref023","doi-asserted-by":"crossref","first-page":"820","DOI":"10.2174\/1389203724666230418123409","article-title":"Bioactive Pentacyclic Triterpenes Trigger multiple signalling pathways for selective apoptosis leading to anticancer efficacy: recent updates and future perspectives","volume":"24","author":"J Banerjee","year":"2023","journal-title":"Curr Protein Pept Sci"},{"issue":"10","key":"pone.0329706.ref024","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1021\/acs.jnatprod.6b00489","article-title":"Arborinane triterpenoids from rubia philippinensis inhibit proliferation and migration of vascular smooth muscle cells induced by the platelet-derived growth factor","volume":"79","author":"KT Quan","year":"2016","journal-title":"J Nat Prod"},{"issue":"10","key":"pone.0329706.ref025","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1158\/1541-7786.MCR-15-0506","article-title":"Phosphoproteomics reveals MAPK inhibitors enhance MET- and EGFR-driven AKT Signaling in KRAS-mutant lung cancer","volume":"14","author":"J-Y Kim","year":"2016","journal-title":"Mol Cancer Res"},{"issue":"3","key":"pone.0329706.ref026","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1124\/mol.109.056598","article-title":"A nondesensitizing kainate receptor point mutant","volume":"76","author":"N Nayeem","year":"2009","journal-title":"Mol Pharmacol"},{"issue":"6","key":"pone.0329706.ref027","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.3892\/mmr.2014.2082","article-title":"Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR-TKI-sensitive, primary resistant and acquired resistant human non-small cell lung cancer cells","volume":"9","author":"M Wu","year":"2014","journal-title":"Mol Med Rep"},{"issue":"6","key":"pone.0329706.ref028","doi-asserted-by":"crossref","DOI":"10.1152\/ajplung.2000.279.6.L1005","article-title":"Reactive oxygen species in cell signaling","volume":"279","author":"VJ Thannickal","year":"2000","journal-title":"Am J Physiol Lung Cell Mol Physiol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0329706","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T17:32:15Z","timestamp":1757352735000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0329706"}},"subtitle":[],"editor":[{"given":"Vino","family":"Cheriyan","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,9,8]]},"references-count":28,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0329706","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2025,9,8]]}}}