title: Novel epigallocatechin gallate (EGCG) analogs activate AMP-activated protein kinase pathway and target cancer stem cells.
abstract: AMP-activated protein kinase (AMPK) is a critical monitor of cellular energy status and also controls processes related to tumor development, including cell cycle progression, protein synthesis, cell growth and survival. Therefore AMPK as an anti-cancer target has received intensive attention recently. It has been reported that the anti-diabetic drug metformin and some natural compounds, such as quercetin, genistein, capsaicin and green tea polyphenol epigallocatechin gallate (EGCG), can activate AMPK and inhibit cancer cell growth. Indeed, natural products have been the most productive source of leads for the development of anti-cancer drugs but perceived disadvantages, such as low bioavailability and week potency, have limited their development and use in the clinic. In this study we demonstrated that synthetic EGCG analogs 4 and 6 were more potent AMPK activators than metformin and EGCG. Activation of AMPK by these EGCG analogs resulted in inhibition of cell proliferation, up-regulation of the cyclin-dependent kinase inhibitor p21, down-regulation of mTOR pathway, and suppression of stem cell population in human breast cancer cells. Our findings suggest that novel potent and specific AMPK activators can be discovered from natural and synthetic sources that have potential to be used for anti-cancer therapy in the clinic.
authors.affiliation: The Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Department of Oncology, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R. Road, Detroit, MI 48201-2013, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Sreedhar
authors.initials: S
authors.lastname: Pamu
authors.forename: Qiuzhi
authors.initials: Q
authors.lastname: Cui
authors.forename: Tak Hang
authors.initials: TH
authors.lastname: Chan
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation
chemical_list: C574186:2,3-naphthalene-1,2,3,4-tetrahydro-2,3-bis(4-aminobenzoate); C574185:2,3-naphthalene-1,2,3,4-tetrahydro-2,3-bis(4-bromo-3,5-dihydroxybenzoate); D000970:Antineoplastic Agents; D001565:Benzoates; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009281:Naphthalenes; D002392:Catechin; C045651:epigallocatechin gallate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases