title: Biological and Mechanistic Characterization of Novel Prodrugs of Green Tea Polyphenol Epigallocatechin Gallate Analogs in Human Leiomyoma Cell Lines.
abstract: Uterine fibroids (leiomyomas) are very common benign tumors grown on the smooth muscle layer of the uterus, present in up to 75% of reproductive-age 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-EGCG or 1) which shows increased stability, bioavailability and biological activity in vivo as compared to EGCG. We also synthesized prodrugs of EGCG analogs, compounds 2a and 4a, in order to potentially reduce their susceptibility to methylation/inhibition by catechol-O-methyltransferase. Here, we determined the effect of EGCG, Pro-EGCG, and 2a and 4a on cultured human uterine leiomyoma cells, and found that 2a and 4a have potent antiproliferative, antiangiogenic, and antifibrotic activities. J. Cell. Biochem. 117: 2357-2369, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan.|Faculty of Veterinary Medicine, Department of Pharmacology, South Valley University, Qena, Egypt.
authors.forename: Reda Saber Ibrahim
authors.initials: RS
authors.lastname: Ahmed
authors.affiliation: Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Chemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Renzetti
authors.affiliation: Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Pershang
authors.initials: P
authors.lastname: Farshi
authors.affiliation: Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Huanjie
authors.initials: H
authors.lastname: Yang
authors.affiliation: Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Claire
authors.initials: C
authors.lastname: Soave
authors.affiliation: Departments of Obstetrics & Gynecology and Anatomy & Cell Biology, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Ghassan
authors.initials: G
authors.lastname: Saed
authors.affiliation: Faculty of Veterinary Medicine, Department of Pharmacology, South Valley University, Qena, Egypt.
authors.forename: Ashraf Ahmed
authors.initials: AA
authors.lastname: El-Ghoneimy
authors.affiliation: Faculty of Veterinary Medicine, Department of Pharmacology, Cairo University, Giza, Egypt.
authors.forename: Hossny Awad
authors.initials: HA
authors.lastname: El-Banna
authors.affiliation: Viteava Pharmaceuticals Inc., Toronto, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Foldes
authors.affiliation: Department of Chemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Tak-Hang
authors.initials: TH
authors.lastname: Chan
authors.affiliation: Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007889:Leiomyoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011355:Prodrugs / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013662:Tea / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
chemical_list: D011355:Prodrugs; D012333:RNA, Messenger; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate
keywords: EGCG ANALOGS; GREEN TEA; LEIOMYOMA; PRODRUGS; THERAPY; UTERINE FIBROIDS