{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:11:00Z","timestamp":1783487460403,"version":"3.55.0"},"reference-count":63,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2016,3,28]],"date-time":"2016-03-28T00:00:00Z","timestamp":1459123200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Canadian Institutes of Health Research (CIHR)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2016,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:label\/><jats:p>Uterine fibroids (leiomyomas) are very common benign tumors grown on the smooth muscle layer of the uterus, present in up to 75% of reproductive\u2010age women and causing significant morbidity in a subset of this population. Although the etiology and biology of uterine fibroids are unclear, strong evidence supports that cell proliferation, angiogenesis and fibrosis are involved in their formation and growth. Currently the only cure for uterine fibroids is hysterectomy; the available alternative therapies have limitations. Thus, there is an urgent need for developing a novel strategy for treating this condition. The green tea polyphenol epigallocatechin gallate (EGCG) inhibits the growth of uterine leiomyoma cells in vitro and in vivo, and the use of a green tea extract (containing 45% EGCG) has demonstrated clinical activity without side effects in women with symptomatic uterine fibroids. However, EGCG has a number of shortcomings, including low stability, poor bioavailability, and high metabolic transformations under physiological conditions, presenting challenges for its development as a therapeutic agent. We developed a prodrug of EGCG (Pro\u2010EGCG or <jats:bold>1<\/jats:bold>) which shows increased stability, bioavailability and biological activity in vivo as compared to EGCG. We also synthesized prodrugs of EGCG analogs, compounds <jats:bold>2a<\/jats:bold> and <jats:bold>4a<\/jats:bold>, in order to potentially reduce their susceptibility to methylation\/inhibition by catechol\u2010<jats:italic>O<\/jats:italic>\u2010methyltransferase. Here, we determined the effect of EGCG, Pro\u2010EGCG, and <jats:bold>2a<\/jats:bold> and <jats:bold>4a<\/jats:bold> on cultured human uterine leiomyoma cells, and found that <jats:bold>2a<\/jats:bold> and <jats:bold>4a<\/jats:bold> have potent antiproliferative, antiangiogenic, and antifibrotic activities. J. Cell. Biochem. 117: 2357\u20132369, 2016. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcb.25533","type":"journal-article","created":{"date-parts":[[2016,3,7]],"date-time":"2016-03-07T15:58:46Z","timestamp":1457366326000},"page":"2357-2369","source":"Crossref","is-referenced-by-count":33,"title":["Biological and Mechanistic Characterization of Novel Prodrugs of Green Tea Polyphenol Epigallocatechin Gallate Analogs in Human Leiomyoma Cell Lines"],"prefix":"10.1002","volume":"117","author":[{"given":"Reda Saber Ibrahim","family":"Ahmed","sequence":"first","affiliation":[{"name":"Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine Wayne State University Detroit Michigan"},{"name":"Faculty of Veterinary Medicine, Department of Pharmacology South Valley University Qena Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Liu","sequence":"additional","affiliation":[{"name":"Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine Wayne State University Detroit Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Renzetti","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pershang","family":"Farshi","sequence":"additional","affiliation":[{"name":"Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine Wayne State University Detroit Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanjie","family":"Yang","sequence":"additional","affiliation":[{"name":"Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine Wayne State University Detroit Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Soave","sequence":"additional","affiliation":[{"name":"Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine Wayne State University Detroit Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghassan","family":"Saed","sequence":"additional","affiliation":[{"name":"Departments of Obstetrics &amp; Gynecology and Anatomy &amp; Cell Biology School of Medicine Wayne State University Detroit Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashraf Ahmed","family":"El\u2010Ghoneimy","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine, Department of Pharmacology South Valley University Qena Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossny Awad","family":"El\u2010Banna","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine, Department of Pharmacology Cairo University Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Foldes","sequence":"additional","affiliation":[{"name":"Viteava Pharmaceuticals Inc. Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tak\u2010Hang","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Q. Ping","family":"Dou","sequence":"additional","affiliation":[{"name":"Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine Wayne State University Detroit Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,3,28]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2003.99"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2011.12.002"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.LAB.0000017499.51216.3E"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0047186"},{"issue":"4","key":"e_1_2_6_6_1","first-page":"487","article-title":"Tea polyphenols, their biological effects and potential molecular targets","volume":"23","author":"Chen D","year":"2008","journal-title":"Histol Histopathol"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/jf300441p"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgt042"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6603(08)60145-2"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2011.21"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.5787"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgt347"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/01635580701365050"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1139\/v07-141"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2009.12.034"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039945"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.201400134"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2007.09.008"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2009.09.011"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.2741\/e363"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.2741\/1595"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2004.08.002"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.106.011460"},{"issue":"2","key":"e_1_2_6_24_1","first-page":"63","article-title":"Inhibition of catechol\u2010O\u2010methyltransferase activity in human breast cancer cells enhances the biological effect of the green tea polyphenol (\u2212)\u2010EGCG","volume":"24","author":"Landis\u2010Piwowar K","year":"2010","journal-title":"Oncol Rep"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2006.11.001"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21124"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-4699"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2010.03.017"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0188"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1080\/01635580801947674"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2014.06.014"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.31.5.572"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.3109\/09513590.2011.583955"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deu123"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-11-0009"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00394-011-0189-0"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-3652"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M004209200"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2011.08.002"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nutres.2007.11.009"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(93)90006-I"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.01.003"},{"issue":"5","key":"e_1_2_6_43_1","first-page":"477","article-title":"Treatment of symptomatic uterine fibroids with green tea extract: A pilot randomized controlled clinical study","volume":"7","author":"Roshdy E","year":"2013","journal-title":"Int J Womens Health"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2012.04.002"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2011.02.007"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmt058"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03402019"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.11325"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddstr.2012.06.001"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2010.04.014"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2011.02.010"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/jf070519f"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1112063"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-012-9299-4"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2007.05.039"},{"issue":"21","key":"e_1_2_6_56_1","first-page":"7526","article-title":"Tea intake, COMT genotype, and breast cancer in Asian\u2010American women","volume":"63","author":"Wu AH","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2011.07.008"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/den417"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.2174\/138945010791170842"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2006.09.037"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2009.08.065"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2009.10.885"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1159\/000363410"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700472"}],"container-title":["Journal of Cellular Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcb.25533","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcb.25533","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcb.25533","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T22:40:17Z","timestamp":1696372817000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcb.25533"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,28]]},"references-count":63,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2016,10]]}},"alternative-id":["10.1002\/jcb.25533"],"URL":"https:\/\/doi.org\/10.1002\/jcb.25533","archive":["Portico"],"relation":{},"ISSN":["0730-2312","1097-4644"],"issn-type":[{"value":"0730-2312","type":"print"},{"value":"1097-4644","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,28]]}}}