{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T17:10:38Z","timestamp":1781889038282,"version":"3.54.5"},"reference-count":44,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,11,21]],"date-time":"2019-11-21T00:00:00Z","timestamp":1574294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["104-2320-B-259-001-MY3"],"award-info":[{"award-number":["104-2320-B-259-001-MY3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Inflammatory bowel disease (IBD) is general term for ulcerative colitis and Crohn\u2019s disease, which is chronic intestinal and colorectal inflammation caused by microbial infiltration or immunocyte attack. IBD is not curable, and is highly susceptible to develop into colorectal cancer. Finding agents to alleviate these symptoms, as well as any progression of IBD, is a critical effort. This study evaluates the anti-inflammation and anti-tumor activity of 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) in in vivo and in vitro assays. The result of an IBD mouse model induced using intraperitoneal chemical azoxymethane (AOM)\/dextran sodium sulfate (DSS) injection showed that intraperitoneal HCD adminstration could ameliorate the inflammatory symptoms of IBD mice. In the in vitro assay, cytotoxic characteristics and retained signaling pathways of HCD treatment were analyzed by MTT assay, cell cycle analysis, and Western blotting. From cell viability determination, the IC50 of HCD in Caco-2 was significantly lower in 2.30 \u03bcM at 48 h when compared to 5-fluorouracil (5-FU) (66.79 \u03bcM). By cell cycle and Western blotting analysis, the cell death characteristics of HCD treatment in Caco-2 exhibited the involvement of extrinsic and intrinsic pathways in cell death, for which intrinsic apoptosis was predominantly activated via the reduction in growth factor signaling. These potential treatments against colon cancer demonstrate that HCD could provide a promising adjuvant as an alternative medicine in combating colorectal cancer and IBD.<\/jats:p>","DOI":"10.3390\/biom9120762","type":"journal-article","created":{"date-parts":[[2019,11,22]],"date-time":"2019-11-22T02:49:27Z","timestamp":1574390967000},"page":"762","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Clerodane Diterpene Ameliorates Inflammatory Bowel Disease and Potentiates Cell Apoptosis of Colorectal Cancer"],"prefix":"10.3390","volume":"9","author":[{"given":"Jia-Huei","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4160-2361","authenticated-orcid":false,"given":"Shian-Ren","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-Jen","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan"},{"name":"Department of Orthopedics, Hualien Armed Force General Hospital, Hualien 97144, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May-Jywan","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei City 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-I","family":"Lue","sequence":"additional","affiliation":[{"name":"Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan"},{"name":"Department of Physiology &amp; Master\u2019s Program, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chen","family":"Chia","sequence":"additional","affiliation":[{"name":"Department of Food Science &amp; Technology, Tajen University, Pingtung 90741, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mindar","family":"Woon","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Yeezen Hospital, Taoyuan 32645, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaw-Syan","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen 361023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9747-8697","authenticated-orcid":false,"given":"Ching-Feng","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen 361023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1111\/jan.13443","article-title":"Colorectal cancer in Taiwan: A case-control retrospective analysis of the impact of a case management programme on refusal and discontinuation of treatment","volume":"74","author":"Chiang","year":"2018","journal-title":"J. Adv. Nurs."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1586\/17474124.2014.924397","article-title":"The role of epigenetics in colorectal cancer","volume":"8","author":"Coppede","year":"2014","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_3","unstructured":"Board, P. (2002). Colon Cancer Treatment (PDQ(R)): Health Professional Version. PDQ Cancer Information Summaries, PDQ Adult Treatment Editorial Board\u2014National Cancer Institute."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"74","DOI":"10.12998\/wjcc.v1.i2.74","article-title":"Biological therapy for dermatological manifestations of inflammatory bowel disease","volume":"1","author":"Zippi","year":"2013","journal-title":"World J. Clin. Cases"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1016\/S0140-6736(17)32448-0","article-title":"Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies","volume":"390","author":"Ng","year":"2017","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nri3661","article-title":"Cytokines in inflammatory bowel disease","volume":"14","author":"Neurath","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1053\/j.gastro.2015.12.036","article-title":"Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers","volume":"150","author":"Robles","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S2468-1253(16)30206-0","article-title":"Effect of psychological therapy on disease activity, psychological comorbidity, and quality of life in inflammatory bowel disease: a systematic review and meta-analysis","volume":"2","author":"Gracie","year":"2017","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1097\/MIB.0000000000001217","article-title":"Inflammatory Bowel Diseases: Review of Known Environmental Protective and Risk Factors Involved","volume":"23","author":"Amini","year":"2017","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/S2468-1253(18)30159-6","article-title":"Differential diagnosis of inflammatory bowel disease: imitations and complications","volume":"3","author":"Gecse","year":"2018","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"629","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":"ref_12","first-page":"62","article-title":"The chemistry, pharmacologic, and therapeutic applications of Polyalthia longifolia","volume":"4","author":"Katkar","year":"2010","journal-title":"Pharm. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1055\/s-0029-1186005","article-title":"6-Hydroxycleroda-3,13-dien-15,16-olide protects neuronal cells from lipopolysaccharide-induced neurotoxicity through the inhibition of microglia-mediated inflammation","volume":"76","author":"Shih","year":"2010","journal-title":"Planta Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.jep.2018.10.001","article-title":"The medicinal uses, toxicities and anti-inflammatory activity of Polyalthia species (Annonaceae)","volume":"229","author":"Yao","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.etap.2016.06.005","article-title":"16-hydroxy-cleroda-3,13-dien-16,15-olide induced glioma cell autophagy via ROS generation and activation of p38 MAPK and ERK-1\/2","volume":"45","author":"Thiyagarajan","year":"2016","journal-title":"Env. Toxicol. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"78379","DOI":"10.18632\/oncotarget.18987","article-title":"The autophagic inhibition oral squamous cell carcinoma cancer growth of 16-hydroxy-cleroda-3,14-dine-15,16-olide","volume":"8","author":"Cheng","year":"2017","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7679","DOI":"10.2147\/OTT.S173378","article-title":"16-Hydroxycleroda-3,13-dien-15,16-olide induces anoikis in human renal cell carcinoma cells: involvement of focal adhesion disassembly and signaling","volume":"11","author":"Chen","year":"2018","journal-title":"Onco Targets"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.phymed.2017.09.021","article-title":"16-Hydroxycleroda-3, 13-dien-15, 16-olide inhibits the proliferation and induces mitochondrial-dependent apoptosis through Akt, mTOR, and MEK-ERK pathways in human renal carcinoma cells","volume":"36","author":"Liu","year":"2017","journal-title":"Phytomedicine"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Velmurugan, B.K., Wang, P.C., and Weng, C.F. (2018). 16-Hydroxycleroda-3,13-dien-15,16-olide and N-Methyl-Actinodaphine Potentiate Tamoxifen-Induced Cell Death in Breast Cancer. Molecules, 23.","DOI":"10.3390\/molecules23081966"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1021\/np000176e","article-title":"Cytotoxic constituents of Polyalthia longifolia var. pendula","volume":"63","author":"Chen","year":"2000","journal-title":"J. Nat. Prod."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/978-1-4939-3603-8_26","article-title":"AOM\/DSS Model of Colitis-Associated Cancer","volume":"Volume 1422","author":"Ivanov","year":"2016","journal-title":"Gastrointestinal Physiology and Diseases"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/978-3-0348-0837-8_2","article-title":"The Role of Inflammation in Colon Cancer","volume":"Volume 816","author":"Aggarwal","year":"2014","journal-title":"Inflammation and Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"378","DOI":"10.3389\/fimmu.2016.00378","article-title":"Crosstalk between Wnt\/beta-Catenin and NF-kappaB Signaling Pathway during Inflammation","volume":"7","author":"Ma","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wheat, C.L., Ko, C.W., Clark-Snustad, K., Grembowski, D., Thornton, T.A., and Devine, B. (2017). Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis. Bmc Gastroenterol., 17.","DOI":"10.1186\/s12876-017-0602-0"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"185","DOI":"10.2147\/DDDT.S11290","article-title":"Current and emerging drugs for the treatment of inflammatory bowel disease","volume":"5","author":"Triantafillidis","year":"2011","journal-title":"Drug Des. Devel."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.phytochem.2015.10.002","article-title":"Phenylpropanoid and lignan glycosides from the aerial parts of Lespedeza cuneata","volume":"121","author":"Zhou","year":"2016","journal-title":"Phytochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"21127","DOI":"10.3390\/molecules191221127","article-title":"Curcumin and inflammatory bowel disease: potential and limits of innovative treatments","volume":"19","author":"Marcuzzi","year":"2014","journal-title":"Molecules"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lewis, S.N., Brannan, L., Guri, A.J., Lu, P., Hontecillas, R., Bassaganya-Riera, J., and Bevan, D.R. (2011). Dietary alpha-eleostearic acid ameliorates experimental inflammatory bowel disease in mice by activating peroxisome proliferator-activated receptor-gamma. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024031"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/imr.12541","article-title":"Caspase-8: regulating life and death","volume":"277","author":"Tummers","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"23996","DOI":"10.18632\/oncotarget.15098","article-title":"Caspase-9: structure, mechanisms and clinical application","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrm3722","article-title":"Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy","volume":"15","author":"Czabotar","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.tox.2011.04.004","article-title":"16-Hydroxycleroda-3,13-dien-15,16-olide deregulates PI3K and Aurora B activities that involve in cancer cell apoptosis","volume":"285","author":"Lin","year":"2011","journal-title":"Toxicology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.lfs.2011.09.011","article-title":"16-hydroxycleroda-3,13-dien-15,16-olide regulates the expression of histone-modifying enzymes PRC2 complex and induces apoptosis in CML K562 cells","volume":"89","author":"Lin","year":"2011","journal-title":"Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1093\/abbs\/gmt144","article-title":"Tumor suppressor p53 and its gain-of-function mutants in cancer","volume":"46","author":"Liu","year":"2014","journal-title":"Acta Biochim. Biophys. Sin. (Shanghai)"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1016\/j.ajpath.2012.06.016","article-title":"p53 mediates TNF-induced epithelial cell apoptosis in IBD","volume":"181","author":"Goretsky","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/DCR.0b013e3181c522c7","article-title":"Tumor necrosis factor alpha induces p53 up-regulated modulator of apoptosis expression in colorectal cancer cell lines","volume":"53","author":"Pastor","year":"2010","journal-title":"Dis. Colon Rectum"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1007\/s10620-015-3646-4","article-title":"Molecular Alterations of Colorectal Cancer with Inflammatory Bowel Disease","volume":"60","author":"Yashiro","year":"2015","journal-title":"Dig. Dis. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e71","DOI":"10.1038\/oncsis.2013.35","article-title":"Epigenetic and genetic features of 24 colon cancer cell lines","volume":"2","author":"Ahmed","year":"2013","journal-title":"Oncogenesis"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4480","DOI":"10.3748\/wjg.v23.i25.4480","article-title":"Expression and role of nuclear receptor coregulators in colorectal cancer","volume":"23","author":"Triki","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.diff.2017.08.003","article-title":"Extrinsic control of Wnt signaling in the intestine","volume":"97","author":"Koch","year":"2017","journal-title":"Differentiation"},{"key":"ref_42","first-page":"505","article-title":"Mesua ferrea stem bark extract induces apoptosis and inhibits metastasis in human colorectal carcinoma HCT 116 cells, through modulation of multiple cell signalling pathways","volume":"15","author":"Asif","year":"2017","journal-title":"Chin. J. Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5511","DOI":"10.1016\/j.bmcl.2013.08.065","article-title":"Anti-proliferative activity of hydnocarpin, a natural lignan, is associated with the suppression of Wnt\/beta-catenin signaling pathway in colon cancer cells","volume":"23","author":"Lee","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jep.2017.07.001","article-title":"Antrodia camphorata inhibits metastasis and epithelial-to-mesenchymal transition via the modulation of claudin-1 and Wnt\/beta-catenin signaling pathways in human colon cancer cells","volume":"208","author":"Hseu","year":"2017","journal-title":"J. Ethnopharmacol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/12\/762\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:36:30Z","timestamp":1760189790000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/12\/762"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,21]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["biom9120762"],"URL":"https:\/\/doi.org\/10.3390\/biom9120762","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,21]]}}}