{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T21:37:41Z","timestamp":1782941861046,"version":"3.54.5"},"reference-count":31,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,11,3]],"date-time":"2018-11-03T00:00:00Z","timestamp":1541203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["RSG-06-163-01"],"award-info":[{"award-number":["RSG-06-163-01"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA009035"],"award-info":[{"award-number":["CA009035"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["T32CA009531"],"award-info":[{"award-number":["T32CA009531"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["CA171000"],"award-info":[{"award-number":["CA171000"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01CA120009"],"award-info":[{"award-number":["1R01CA120009"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R03CA112625"],"award-info":[{"award-number":["5R03CA112625"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01GM088249"],"award-info":[{"award-number":["1R01GM088249"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["awarded to Tak-Hang Chan"],"award-info":[{"award-number":["awarded to Tak-Hang Chan"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The 5\u2032-3\u2032 structure-specific endonuclease ERCC1\/XPF (Excision Repair Cross-Complementation Group 1\/Xeroderma Pigmentosum group F) plays critical roles in the repair of cisplatin-induced DNA damage. As such, it has been identified as a potential pharmacological target for enhancing clinical response to platinum-based chemotherapy. The goal of this study was to follow up on our previous identification of the compound NSC143099 as a potent inhibitor of ERCC1\/XPF activity by performing an in silico screen to identify structural analogues that could inhibit ERCC1\/XPF activity in vitro and in vivo. Using a fluorescence-based DNA-endonuclease incision assay, we identified the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) as a potent inhibitor of ERCC1\/XPF activity with an IC50 (half maximal inhibitory concentration) in the nanomolar range in biochemical assays. Using DNA repair assays and clonogenic survival assays, we show that EGCG can inhibit DNA repair and enhance cisplatin sensitivity in human cancer cells. Finally, we show that a prodrug of EGCG, Pro-EGCG (EGCG octaacetate), can enhance response to platinum-based chemotherapy in vivo. Together these data support a novel target of EGCG in cancer cells, namely ERCC1\/XPF. Our studies also corroborate previous observations that EGCG enhances sensitivity to cisplatin in multiple cancer types. Thus, EGCG or its prodrug makes an ideal candidate for further pharmacological development with the goal of enhancing cisplatin response in human tumors.<\/jats:p>","DOI":"10.3390\/nu10111644","type":"journal-article","created":{"date-parts":[[2018,11,5]],"date-time":"2018-11-05T10:43:45Z","timestamp":1541414625000},"page":"1644","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Targeting the DNA Repair Endonuclease ERCC1-XPF with Green Tea Polyphenol Epigallocatechin-3-Gallate (EGCG) and Its Prodrug to Enhance Cisplatin Efficacy in Human Cancer Cells"],"prefix":"10.3390","volume":"10","author":[{"given":"Joshua R.","family":"Heyza","sequence":"first","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeevani","family":"Arora","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayla L.","family":"Conner","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley M.","family":"Floyd","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul R.","family":"Deshmukh","sequence":"additional","affiliation":[{"name":"Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Sarver","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Trabbic","sequence":"additional","affiliation":[{"name":"Center for Drug Design and Development, Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Erhardt","sequence":"additional","affiliation":[{"name":"Center for Drug Design and Development, Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8702-4499","authenticated-orcid":false,"given":"Tak-Hang","family":"Chan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China"},{"name":"Department of Chemistry, McGill University, Montreal, QC H3A 0B8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Q. Ping","family":"Dou","sequence":"additional","affiliation":[{"name":"Departments of Oncology, Pharmacology, and Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve M.","family":"Patrick","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nrc2167","article-title":"The resurgence of platinum-based cancer chemotherapy","volume":"7","author":"Kelland","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9990","DOI":"10.1093\/nar\/gks818","article-title":"DNA repair endonuclease ERCC1-XPF as a novel therapeutic target to overcome chemoresistance in cancer therapy","volume":"40","author":"McNeil","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.dnarep.2010.03.010","article-title":"Downregulation of XPF-ERCC1 enhances cisplatin efficacy in cancer cells","volume":"9","author":"Arora","year":"2010","journal-title":"DNA Repair"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.3109\/10409230903501819","article-title":"DNA interstrand crosslink repair in mammalian cells: Step by step","volume":"45","author":"Muniandy","year":"2010","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.dnarep.2014.03.018","article-title":"Mechanism and regulation of incisions during DNA interstrand cross-link repair","volume":"19","author":"Zhang","year":"2014","journal-title":"DNA Repair"},{"key":"ref_6","first-page":"2286","article-title":"Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer","volume":"8","author":"Lord","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1056\/NEJMoa060570","article-title":"DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy","volume":"355","author":"Olaussen","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1200\/JCO.2012.46.9783","article-title":"Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine\/carboplatin in advanced non-small-cell lung cancer","volume":"31","author":"Bepler","year":"2013","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1056\/NEJMoa1214271","article-title":"ERCC1 isoform expression and DNA repair in non-small-cell lung cancer","volume":"368","author":"Friboulet","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/em.20583","article-title":"Multiple roles of ERCC1-XPF in mammalian interstrand crosslink repair","volume":"51","author":"Rahn","year":"2010","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4104","DOI":"10.1016\/j.bmcl.2015.08.024","article-title":"N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF","volume":"25","author":"Chapman","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1016\/j.bmcl.2015.08.031","article-title":"Catechols and 3-hydroxypyridones as inhibitors of the DNA repair complex ERCC1-XPF","volume":"25","author":"Chapman","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.dnarep.2015.04.002","article-title":"Inhibition of the ERCC1-XPF structure-specific endonuclease to overcome cancer chemoresistance","volume":"31","author":"McNeil","year":"2015","journal-title":"DNA Repair"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"75104","DOI":"10.18632\/oncotarget.12072","article-title":"Identification of small molecule inhibitors of ERCC1-XPF that inhibit DNA repair and potentiate cisplatin efficacy in cancer cells","volume":"7","author":"Arora","year":"2016","journal-title":"Oncotarget"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jphs.2015.04.003","article-title":"EGCG synergizes the therapeutic effect of cisplatin and oxaliplatin through autophagic pathway in human colorectal cancer cells","volume":"128","author":"Hu","year":"2015","journal-title":"J. Pharmacol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wang, X., Jiang, P., Wang, P., Yang, C.S., Wang, X., and Feng, Q. (2015). EGCG enhances cisplatin sensitivity by regulating expression of the copper and cisplatin influx transporter ctr1 in ovary cancer. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132086"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1002\/tox.22284","article-title":"Epigallocatechin gallate sensitizes cisplatin-resistant oral cancer CAR cell apoptosis and autophagy through stimulating AKT\/STAT3 pathway and suppressing multidrug resistance 1 signaling","volume":"32","author":"Yuan","year":"2017","journal-title":"Environ. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"296","DOI":"10.2174\/156800911794519743","article-title":"Green tea polyphenols as proteasome inhibitors: Implication in chemoprevention","volume":"11","author":"Yang","year":"2011","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13322","DOI":"10.1074\/jbc.M004209200","article-title":"Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo","volume":"276","author":"Nam","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12658","DOI":"10.1021\/bi801883v","article-title":"Pseudoirreversible inhibition of prostate-specific membrane antigen by phosphoramidate peptidomimetics","volume":"47","author":"Liu","year":"2008","journal-title":"Biochemistry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.dnarep.2017.01.002","article-title":"Differential role of base excision repair proteins in mediating cisplatin cytotoxicity","volume":"51","author":"Sawant","year":"2017","journal-title":"DNA Repair"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7332","DOI":"10.1093\/nar\/gkt479","article-title":"Epistatic role of base excision repair and mismatch repair pathways in mediating cisplatin cytotoxicity","volume":"41","author":"Kothandapani","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5587","DOI":"10.1016\/j.bmc.2004.08.002","article-title":"A potential prodrug for a green tea polyphenol proteasome inhibitor: Evaluation of the peracetate ester of (-)-epigallocatechin gallate [(-)-EGCG]","volume":"12","author":"Lam","year":"2004","journal-title":"Bioorg. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13321-015-0069-3","article-title":"Why is Tanimoto index an appropriate choice for fingerprint-based similarity calculations?","volume":"7","author":"Bajusz","year":"2015","journal-title":"J. Cheminform."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S0027-5107(02)00336-6","article-title":"Cancer chemopreventive activity and bioavailability of tea and tea polyphenols","volume":"523","author":"Lambert","year":"2003","journal-title":"Mutat. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4151","DOI":"10.1021\/jf000386x","article-title":"Identification of biliary metabolites of (-)-epigallocatechin gallate in rats","volume":"48","author":"Kida","year":"2000","journal-title":"J. Agric. Food Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4303","DOI":"10.1158\/0008-5472.CAN-06-4699","article-title":"A novel prodrug of the green tea polyphenol (-)-epigallocatechin-3-gallate as a potential anticancer agent","volume":"67","author":"Huo","year":"2007","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Simeonov, A., Kulkarni, A., Dorjsuren, D., Jadhav, A., Shen, M., McNeill, D.R., Austin, C.P., and Wilson, D.M. (2009). Identification and characterization of inhibitors of human apurinic\/apyrimidinic endonuclease APE1. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005740"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1093\/carcin\/bgm110","article-title":"Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1","volume":"28","author":"Lee","year":"2007","journal-title":"Carcinogenesis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/S1097-2765(05)00089-4","article-title":"Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine","volume":"6","author":"Walker","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/B978-0-12-385855-9.00007-2","article-title":"EGCG, green tea polyphenols and their synthetic analogs and prodrugs for human cancer prevention and treatment","volume":"53","author":"Chen","year":"2011","journal-title":"Adv. Clin. Chem."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/10\/11\/1644\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:27:46Z","timestamp":1760196466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/10\/11\/1644"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,3]]},"references-count":31,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2018,11]]}},"alternative-id":["nu10111644"],"URL":"https:\/\/doi.org\/10.3390\/nu10111644","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,3]]}}}