title: Synthetic peracetate tea polyphenols as potent proteasome inhibitors and apoptosis inducers in human cancer cells.
abstract: It has been suggested that proteasome activity is essential for tumor cell proliferation and drug resistance development. We have previously shown that natural and synthetic ester bond-containing tea polyphenols are selective inhibitors of the chymotrypsin-like activity of the proteasome. The most abundant catechin in green tea is (-)-epigallocatechin-3-gallate [(-)-EGCG], which has been found by many laboratories to exhibit the most potent anticancer activity. We have reported that (-)-EGCG is also the most effective proteasome inhibitor among all the natural green tea catechins tested. Unfortunately, (-)-EGCG is very unstable in neutral and alkaline conditions. In an attempt to increase the stability and thus the efficacy, we synthesized several (-)-EGCG analogs with acetyl protected -OH groups as prodrugs. Here we report, for the first time, that these acetylated synthetic tea analogs are much more potent than natural (-)-EGCG in inhibiting the proteasome in cultured tumor cells. Consistently, these protected analogs showed much higher potency than (-)-EGCG to inhibit proliferation and transforming activity and to induce apoptosis in human leukemic, prostate, breast, and simian virus 40-transformed cells. Additionally, these protected analogs had greatly reduced effects on human normal and non-transformed cells. Therefore, these peracetate protected tea polyphenols are more efficacious than (-)-EGCG and possess great potential to be developed into novel anticancer drugs. Identification of the cytosolic metabolite(s) of peracetate-protected polyphenols in cultured tumor cells and examination of their in vivo tumor growth-inhibitory activity are currently underway in our laboratory.
authors.affiliation: The Prevention Program, Barbara Ann Karmanos Cancer Institute and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kuhn
authors.forename: Wai Har
authors.initials: WH
authors.lastname: Lam
authors.forename: Aslamuzzaman
authors.initials: A
authors.lastname: Kazi
authors.forename: Kenyon G
authors.initials: KG
authors.lastname: Daniel
authors.forename: Shuojing
authors.initials: S
authors.lastname: Song
authors.forename: Larry M C
authors.initials: LM
authors.lastname: Chow
authors.forename: Tak Hang
authors.initials: TH
authors.lastname: Chan
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D005419:Flavonoids / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019169:Jurkat Cells; D010636:Phenols / Q000138:chemical synthesis* / Q000494:pharmacology; D059808:Polyphenols; D061988:Proteasome Inhibitors; D013662:Tea / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D061988:Proteasome Inhibitors; D013662:Tea; D002392:Catechin; D006861:Hydrogen Peroxide; C045651:epigallocatechin gallate