{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T11:54:01Z","timestamp":1791633241365,"version":"4.3.4"},"reference-count":39,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2019,10,16]],"date-time":"2019-10-16T00:00:00Z","timestamp":1571184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Pseudolaric Acid B (PAB), diterpenoid isolated from the root bark of Pseudolarix kaempferi Gordon tree (Pinaceae), exhibits an anti-proliferative and apoptotic activity in various cancer cell lines but to date, the effects of PAB on head and neck cancer (HNC) cell lines remain to be elucidated. In this study, we showed that PAB significantly inhibited the viability and caspase-dependent apoptosis in HN22 cell line. PAB-induced apoptosis is through inducing death receptor 5 (DR5) together with the increase in the expression of cleaved caspase-8. It also inhibited the proliferations and induced apoptosis through DR5 in other three HNC cell lines (HSC3, Ca9.22, and HSC4). Extending our in vitro findings, we found that ethanol extract of Pseudolarix kaempferi (2.5 mg\/kg\/day) reduced tumor growth in a xenograft model bearing HN22 cell line without any change in body weight. DR5 were also found to be increased in tumors tissue of PAB-treated mice without any apparent histopathological changes in liver or kidney tissues. Taken together, PAB may be a potential lead compound for chemotherapeutic agents against head and neck cancer.<\/jats:p>","DOI":"10.3390\/molecules24203715","type":"journal-article","created":{"date-parts":[[2019,10,17]],"date-time":"2019-10-17T04:46:06Z","timestamp":1571287566000},"page":"3715","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Pseudolaric Acid B Induces Growth Inhibition and Caspase-Dependent Apoptosis on Head and Neck Cancer Cell lines through Death Receptor 5"],"prefix":"10.3390","volume":"24","author":[{"given":"Su-Jung","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Hyun","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Hyoung","family":"Yang","sequence":"additional","affiliation":[{"name":"Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohwan","family":"Jin","sequence":"additional","affiliation":[{"name":"Laboratory Animal Center, CHA University, CHA Biocomplex, Sampyeong-dong, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won Woo","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory Animal Center, CHA University, CHA Biocomplex, Sampyeong-dong, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Hoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Hye","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeti","family":"Swarup","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoung-Ok","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Ae","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam-Tae","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of ChemBio Specialization Program (CK-II), Dankook University, Cheonan 31116, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Doo","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Il","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8670-9579","authenticated-orcid":false,"given":"Sung-Dae","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,16]]},"reference":[{"key":"ref_1","first-page":"394","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA: A Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4523","DOI":"10.2147\/CMAR.S171251","article-title":"Trends in clinical features and survival of oral cavity cancer: Fifty years of experience with 3,362 consecutive cases from a single institution","volume":"10","author":"Chen","year":"2018","journal-title":"Cancer Manag. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1007\/s12663-018-1166-4","article-title":"Global Scenario of Research in Oral Cancer","volume":"18","author":"Sreekumar","year":"2019","journal-title":"J. Maxillofac. Oral Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1021\/np200906s","article-title":"Natural products as sources of new drugs over the 30 years from 1981 to 2010","volume":"75","author":"Newman","year":"2012","journal-title":"J. Nat. Prod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1007\/s40265-015-0489-4","article-title":"Recent advances in the development of antineoplastic agents derived from natural products","volume":"75","author":"Trendowski","year":"2015","journal-title":"Drugs"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1055\/s-2006-960989","article-title":"The cytotoxic principles of Pseudolarix kaempferi: Pseudolaric acid-A and -B and related derivatives","volume":"56","author":"Pan","year":"1990","journal-title":"Planta Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1039\/b906520m","article-title":"Pseudolaric acids: Isolation, bioactivity and synthetic studies","volume":"7","author":"Chiu","year":"2010","journal-title":"Nat. Prod. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zhang, H., Li, J.-C., Luo, H., Zhao, L., Zhang, Z.-D., and Shen, X.-F. (2018). Pseudolaric acid B exhibits anti-cancer activity on human hepatocellular carcinoma through inhibition of multiple carcinogenic signaling pathways. Phytomedicine, 59.","DOI":"10.1016\/j.phymed.2018.11.019"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"20","DOI":"10.3349\/ymj.2018.59.1.20","article-title":"Pseudolaric Acid B Inhibits Proliferation, Invasion and Epithelial-to-Mesenchymal Transition in Human Pancreatic Cancer Cell","volume":"59","author":"Li","year":"2018","journal-title":"Yonsei Med. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1097\/CAD.0000000000000500","article-title":"Pseudolaric acid B induces endometrial cancer Ishikawa cell apoptosis and inhibits metastasis through AKT-GSK-3beta and ERK1\/2 signaling pathways","volume":"28","author":"Wang","year":"2017","journal-title":"Anticancer Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3389\/fphar.2017.00394","article-title":"A Systematic Review of the Immune-Regulating and Anticancer Activities of Pseudolaric Acid B","volume":"8","author":"Liu","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.3892\/mmr.2015.3615","article-title":"Pseudolaric acid B exerts antitumor activity via suppression of the Akt signaling pathway in HeLa cervical cancer cells","volume":"12","author":"Li","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"849","DOI":"10.3892\/or.2013.2869","article-title":"Pseudolaric acid B induces caspase-dependent cell death in human ovarian cancer cells","volume":"31","author":"Yu","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3892\/mmr.2013.1800","article-title":"Role of pseudolaric acid B in A549 lung cancer cell proliferation and apoptosis","volume":"9","author":"Guan","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1002\/ptr.4808","article-title":"Pseudolaric acid B induces caspase-dependent apoptosis and autophagic cell death in prostate cancer cells","volume":"27","author":"Tong","year":"2013","journal-title":"Phytother. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Khan, M., Zheng, B., Yi, F., Rasul, A., Gu, Z., Li, T., Gao, H., Qazi, J.I., Yang, H., and Ma, T. (2012). Pseudolaric Acid B induces caspase-dependent and caspase-independent apoptosis in u87 glioblastoma cells. Evid. Based Complement. Alternat. Med., 2012.","DOI":"10.1155\/2012\/957568"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4236\/jct.2012.31001","article-title":"The Apoptotic Effect of the Methanol Extract of Polygonum cuspidatum through Up-Regulation Death Receptor 5 and CHOP in HSC-2 Human Oral Cancer Cells","volume":"3","author":"Yu","year":"2012","journal-title":"J. Cancer Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1111\/j.1601-0825.2012.01905.x","article-title":"\u03b2-Phenethyl isothiocyanate induces death receptor 5 to induce apoptosis in human oral cancer cells via p38","volume":"18","author":"Huong","year":"2012","journal-title":"Oral Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"663","DOI":"10.3892\/mmr.2013.1826","article-title":"Extracellular signal-regulated kinase inhibition is required for methanol extract of Smilax china L.-induced apoptosis through death receptor 5 in human oral mucoepidermoid carcinoma cells","volume":"9","author":"Yu","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1097\/CEJ.0b013e32834473c3","article-title":"Chemopreventive effects of synthetic C-substituted diindolylmethanes originating from cruciferous vegetables in human oral cancer cells","volume":"20","author":"Shin","year":"2011","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Katiyar, S. (2016). Emerging phytochemicals for the prevention and treatment of head and neck cancer. Molecules, 21.","DOI":"10.3390\/molecules21121610"},{"key":"ref_22","first-page":"987","article-title":"Procurement of plant materials for antitumor screening","volume":"60","author":"Perdue","year":"1976","journal-title":"Cancer. Treat. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1111\/eos.12387","article-title":"Oridonin induces apoptosis in human oral cancer cells via phosphorylation of histone H2 AX","volume":"125","author":"Yang","year":"2017","journal-title":"Eur. J. Oral Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.archoralbio.2017.09.024","article-title":"Apoptosis induced by caffeic acid phenethyl ester in human oral cancer cell lines: Involvement of Puma and Bax activation","volume":"84","author":"Yu","year":"2017","journal-title":"Arch. Oral Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"91306","DOI":"10.18632\/oncotarget.20444","article-title":"Nitidine chloride acts as an apoptosis inducer in human oral cancer cells and a nude mouse xenograft model via inhibition of STAT3","volume":"8","author":"Kim","year":"2017","journal-title":"Oncotarget."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6002","DOI":"10.1158\/1078-0432.CCR-05-0209","article-title":"Pseudolaric acid B, a novel microtubule-destabilizing agent that circumvents multidrug resistance phenotype and exhibits antitumor activity in vivo","volume":"11","author":"Wong","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1124\/mol.105.020537","article-title":"Pseudolarix acid B, a new tubulin-binding agent, inhibits angiogenesis by interacting with a novel binding site on tubulin","volume":"69","author":"Tong","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/aps.2016.8","article-title":"Activation of p53 contributes to pseudolaric acid B-induced senescence in human lung cancer cells in vitro","volume":"37","author":"Yao","year":"2016","journal-title":"Acta. Pharmacol. Sin."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/emm.2006.50","article-title":"Involvement of JNK-initiated p53 accumulation and phosphorylation of p53 in pseudolaric acid B induced cell death","volume":"38","author":"Gong","year":"2006","journal-title":"Exp. Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.abb.2014.05.029","article-title":"ATM-p53 pathway causes G2\/M arrest, but represses apoptosis in pseudolaric acid B-treated HeLa cells","volume":"558","author":"Yao","year":"2014","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1111\/j.1745-7254.2008.00835.x","article-title":"Protein tyrosine kinase, JNK, and ERK involvement in pseudolaric acid B-induced apoptosis of human breast cancer MCF-7 cells","volume":"29","author":"Yu","year":"2008","journal-title":"Acta. Pharmacol. Sin."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.3892\/ijo.2015.3204","article-title":"Goniothalamin enhances TRAIL-induced apoptosis in colorectal cancer cells through DR5 upregulation and cFLIP downregulation","volume":"47","author":"Sophonnithiprasert","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1158\/0008-5472.CAN-13-2081","article-title":"Mechanistic elucidation of the antitumor properties of withaferin a in breast cancer","volume":"74","author":"Nagalingam","year":"2014","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Won, D.H., Kim, L.H., Jang, B., Yang, I.H., Kwon, H.J., Jin, B., Oh, S.H., Kang, J.H., Hong, S.D., and Shin, J.A. (2018). In vitro and in vivo anti-cancer activity of silymarin on oral cancer. Tumour Biol., 40.","DOI":"10.1177\/1010428318776170"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/jop.12353","article-title":"Anticancer activity of Ashwagandha against human head and neck cancer cell lines","volume":"45","author":"Lee","year":"2016","journal-title":"J. Oral Pathol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.oraloncology.2015.03.003","article-title":"Induction of apoptosis by parthenolide in human oral cancer cell lines and tumor xenografts","volume":"51","author":"Yu","year":"2015","journal-title":"Oral Oncol"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.yexcr.2017.01.012","article-title":"Pseudolaric acid B inhibits gastric cancer cell metastasis in vitro and in haematogenous dissemination model through PI3K\/AKT, ERK1\/2 and mitochondria-mediated apoptosis pathways","volume":"352","author":"Wang","year":"2017","journal-title":"Exp. Cell Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.tiv.2012.02.004","article-title":"Pseudolaric acid B induces apoptosis via proteasome-mediated Bcl-2 degradation in hormone-refractory prostate cancer DU145 cells","volume":"26","author":"Zhao","year":"2012","journal-title":"Toxicol Vitr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1111\/j.1745-7254.2007.00706.x","article-title":"Pseudolaric acid B induces apoptosis, senescence, and mitotic arrest in human breast cancer MCF-7","volume":"28","author":"Yu","year":"2007","journal-title":"Acta. Pharmacol. Sin."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/20\/3715\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:26:41Z","timestamp":1760189201000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/20\/3715"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,16]]},"references-count":39,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["molecules24203715"],"URL":"https:\/\/doi.org\/10.3390\/molecules24203715","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,16]]}}}