{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:00:40Z","timestamp":1792641640588,"version":"4.5.0"},"reference-count":35,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Farrerol (FA) is a flavanone isolated from the Chinese herbal medicine \u201cMan-shan-hong\u201d (Rhododendron dauricum L.). In the present study, FA decreased the viability of SKOV3 cells in a dose- and time-dependent manner, and it induced G2\/M cell cycle arrest and cell apoptosis. Cell cycle distribution analysis via flow cytometry showed that FA decreased G1 populations and increased G2\/M populations in SKOV3 cells. Additionally, Western blotting confirmed an increase in the expression level of proteins involved in the cell cycle, e.g., CDK and cyclins. FA-induced apoptosis in SKOV3 cells was also investigated using a TUNEL assay, and increased expression levels of proapoptotic factors, including Caspase-3 and poly ADP ribose polymerase (PARP), through the Extracellular signal-regulated kinase (ERK)\/MAPK pathway were investigated. Proinflammatory cytokines (e.g., IL-6, TNF-\u03b1, and IL-1) have been identified as a driver of the pathological mechanisms underlying involuntary weight loss and impaired physical function, i.e., cachexia, during cancer; in the present study, we showed that farrerol attenuates TNF-\u03b1-induced lipolysis and increases adipogenic differentiation in 3T3-L1 cells. Thus, farrerol could potentially be used as an anticancer agent or anticachetic drug.<\/jats:p>","DOI":"10.3390\/ijms22179400","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T11:01:37Z","timestamp":1630321297000},"page":"9400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Farrerol Induces Cancer Cell Death via ERK Activation in SKOV3 Cells and Attenuates TNF-\u03b1-Mediated Lipolysis"],"prefix":"10.3390","volume":"22","author":[{"given":"Jongbeom","family":"Chae","sequence":"first","affiliation":[{"name":"Department of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"National Development Institute of Korean Medicine, 94, Gyeongju-si 38540, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"seok tae","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 42415, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8186-0886","authenticated-orcid":false,"given":"Seul Gi","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea"},{"name":"Center for Forensic Pharmaceutical Science, Keimyung University, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2166-432X","authenticated-orcid":false,"given":"Oyindamola Vivian","family":"Ojulari","sequence":"additional","affiliation":[{"name":"Department of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Jin","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 42415, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1204-2059","authenticated-orcid":false,"given":"Taeg Kyu","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea"},{"name":"Center for Forensic Pharmaceutical Science, Keimyung University, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju-Ock","family":"Nam","sequence":"additional","affiliation":[{"name":"Department of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Korea"},{"name":"Institute of Agricultural Science & Technology, Kyungpook National University, Daegu 41566, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.clon.2005.05.009","article-title":"Epithelial Ovarian Cancer: A Review of Current Management","volume":"17","author":"Guppy","year":"2005","journal-title":"Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1158\/1055-9965.98.14.1","article-title":"Endogenous Hormones and Ovarian Cancer: Epidemiology and Current Hypotheses","volume":"14","author":"Lukanova","year":"2005","journal-title":"Cancer Epidemiol. Prev. Biomark."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Permuth-Wey, J., and Sellers, T.A. (2009). Epidemiology of ovarian cancer. Cancer Epidemiol., 413\u2013437.","DOI":"10.1007\/978-1-60327-492-0_20"},{"key":"ref_4","first-page":"3620","article-title":"Mechanisms of Taxol-induced Cell Death Are Concentration Dependent","volume":"58","author":"Torres","year":"1998","journal-title":"Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"305","DOI":"10.3892\/or.2013.2815","article-title":"Induction of G2\/M phase cell cycle arrest and apoptosis by ginsenoside Rf in human osteosarcoma MG-63 cells through the mitochondrial pathway","volume":"31","author":"Shangguan","year":"2014","journal-title":"Oncol Rep"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1080\/01926230701320337","article-title":"Apoptosis: A review of programmed cell death","volume":"35","author":"Elmore","year":"2007","journal-title":"Toxicol. Pathol."},{"key":"ref_7","first-page":"4767","article-title":"Fluoride Induces Apoptosis in Mammalian Cells: In Vitro and In Vivo Studies","volume":"37","author":"Ribeiro","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"147","DOI":"10.4161\/cbt.4.2.1508","article-title":"Overview of cell death signaling pathways","volume":"4","author":"Jin","year":"2005","journal-title":"Cancer Biol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1097\/CEJ.0000000000000212","article-title":"Sustained ERK activation-mediated proliferation inhibition of farrerol on human gastric carcinoma cell line by G0\/G1-phase cell-cycle arrest","volume":"25","author":"Liu","year":"2016","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1097\/CEJ.0000000000000104","article-title":"Apoptosis induced by farrerol in human gastric cancer SGC-7901 cells through the mitochondrial-mediated pathway","volume":"24","author":"Liu","year":"2015","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/sj.cr.7290105","article-title":"MAPK signal pathways in the regulation of cell proliferation in mammalian cells","volume":"12","author":"Zhang","year":"2002","journal-title":"Cell Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Braicu, C., Buse, M., Busuioc, C., Drula, R., Gulei, D., Raduly, L., Rusu, A., Irimie, A., Atanasov, A.G., and Slaby, O. (2019). A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer. Cancers, 11.","DOI":"10.3390\/cancers11101618"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6158","DOI":"10.1038\/sj.onc.1203173","article-title":"Diverse functions of JNK signaling and c-Jun in stress response and apoptosis","volume":"18","author":"Bohmann","year":"1999","journal-title":"Oncogene"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e200","DOI":"10.1038\/oncsis.2016.3","article-title":"Understanding cachexia as a cancer metabolism syndrome","volume":"5","author":"Porporato","year":"2016","journal-title":"Oncogenesis"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Aust, S., Knogler, T., Pils, D., Obermayr, E., Reinthaller, A., Zahn, L., Radlgruber, I., Mayerhoefer, M.E., Grimm, C., and Polterauer, S. (2015). Skeletal Muscle Depletion and Markers for Cancer Cachexia Are Strong Prognostic Factors in Epithelial Ovarian Cancer. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0140403"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s13048-019-0586-1","article-title":"Withaferin A ameliorates ovarian cancer-induced cachexia and proinflammatory signaling","volume":"12","author":"Straughn","year":"2019","journal-title":"J. Ovarian Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1006\/gyno.1996.0008","article-title":"Aberrations in Normal Systemic Lipid Metabolism in Ovarian Cancer Patients","volume":"60","author":"Doering","year":"1996","journal-title":"Gynecol. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1210\/endo.136.4.7895657","article-title":"Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells","volume":"136","author":"Szalkowski","year":"1995","journal-title":"Endocrinology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1007\/s00125-004-1503-7","article-title":"Rosiglitazone ameliorates insulin resistance in brown adipocytes of Wistar rats by impairing TNF-\u03b1 induction of p38 and p42\/p44 mitogen-activated protein kinases","volume":"47","author":"Hernandez","year":"2004","journal-title":"Diabetologia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1053\/meta.2001.19505","article-title":"Thiazolidinedione-and tumor necrosis factor alpha\u2013induced downregulation of peroxisome proliferator\u2013activated receptor gamma mRNA in differentiated 3T3-L1 adipocytes","volume":"50","author":"Perrey","year":"2001","journal-title":"Metab. Clin. Exp."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.2337\/diabetes.50.5.1083","article-title":"Pioglitazone Ameliorates Tumor Necrosis Factor-\u03b1\u2013Induced Insulin Resistance by a Mechanism Independent of Adipogenic Activity of Peroxisome Proliferator\u2013Activated Receptor-\u03b3","volume":"50","author":"Iwata","year":"2001","journal-title":"Diabetes"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1210\/endo.135.5.7956951","article-title":"Troglitazone prevents the inhibitory effects of inflammatory cytokines on insulin-induced adipocyte differentiation in 3T3-L1 cells","volume":"135","author":"Ohsumi","year":"1994","journal-title":"Endocrinology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.fct.2017.05.032","article-title":"Regulatory effects of 4-methoxychalcone on adipocyte differentiation through PPAR\u03b3 activation and reverse effect on TNF-\u03b1 in 3T3-L1 cells","volume":"106","author":"Han","year":"2017","journal-title":"Food Chem. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S1570-0232(04)00549-5","article-title":"Chromatographic and electrophoretic methods for pharmaceutically active compounds in Rhododendron dauricum","volume":"812","author":"Cao","year":"2004","journal-title":"J. Chromatogr. B"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ci, X., Chu, X., Wei, M., Yang, X., Cai, Q., and Deng, X. (2012). Different Effects of Farrerol on an OVA-Induced Allergic Asthma and LPS-induced Acute Lung Injury. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034634"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.phymed.2016.03.008","article-title":"Farrerol inhibited angiogenesis through Akt\/mTOR, Erk and Jak2\/Stat3 signal pathway","volume":"23","author":"Dai","year":"2016","journal-title":"Phytomedicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/aps.2011.1","article-title":"Involvement of estrogen receptor-\u03b2 in farrerol inhibition of rat thoracic aorta vascular smooth muscle cell proliferation","volume":"32","author":"Li","year":"2011","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/j.1574-6968.2010.02183.x","article-title":"Subinhibitory concentrations of farrerol reduce \u03b1-toxin expression in Staphylococcus aureus","volume":"315","author":"Qiu","year":"2011","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yue, J., and L\u00f3pez, J.M. (2020). Understanding MAPK Signaling Pathways in Apoptosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072346"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"127","DOI":"10.4103\/0971-5916.93435","article-title":"Association of TNF-\u03b1 with insulin resistance in type 2 diabetes mellitus","volume":"135","author":"Swaroop","year":"2012","journal-title":"Indian J. Med. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"37865","DOI":"10.1074\/jbc.M306376200","article-title":"Degradation of Cyclin B Is Required for the Onset of Anaphase in Mammalian Cells*","volume":"278","author":"Chang","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1098\/rstb.1999.0500","article-title":"Mechanisms and regulation of the degradation of cyclin B","volume":"354","author":"Hunt","year":"1999","journal-title":"Trans. R. Soc. Lond. Ser. B Biol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.3892\/ijo.2012.1619","article-title":"Antitumor activity of AZ64 via G2\/M arrest in non-small cell lung cancer","volume":"41","author":"Xue","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.lfs.2016.11.033","article-title":"TNF-\u03b1 and cancer cachexia: Molecular insights and clinical implications","volume":"170","author":"Patel","year":"2017","journal-title":"Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"16284","DOI":"10.18632\/oncotarget.24616","article-title":"A novel herbal formula, SGE, induces endoplasmic reticulum stress-mediated cancer cell death and alleviates cachexia symptoms induced by colon-26 adenocarcinoma","volume":"9","author":"Kim","year":"2018","journal-title":"Oncotarget"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9400\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:55:39Z","timestamp":1760165739000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9400"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,30]]},"references-count":35,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22179400"],"URL":"https:\/\/doi.org\/10.3390\/ijms22179400","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,30]]}}}