title: Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system.
abstract: Gambogic acid (GA), displays cytotoxicity towards a wide variety of tumor cells and has been shown to affect many important cell-signaling pathways. In the present work, we investigated the mechanism of action of GA by analysis of drug-induced changes in gene expression profiles and identified GA and the derivative dihydro GA as possible inhibitors of the ubiquitin-proteasome system (UPS). Both GA and dihydro GA inhibited proteasome function in cells resulting in the accumulation of polyubiquitin complexes. In vitro experiments showed that both GA and dihydro GA inhibited 20S chymotrypsin activity and the inhibitory effects of GA and dihydro GA on proteasome function corresponded with apoptosis induction and cell death. In conclusion, our results show that GA and dihydro GA exert their cytotoxic activity through inhibition of the UPS, specifically by acting as inhibitors of the chymotrypsin activity of the 20S proteasome.
authors.affiliation: Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Center, Uppsala University, Uppsala, Sweden. jenny@felth.se
authors.forename: Jenny
authors.initials: J
authors.lastname: Felth
authors.forename: Karolina
authors.initials: K
authors.lastname: Lesiak-Mieczkowska
authors.forename: Padraig
authors.initials: P
authors.lastname: D'Arcy
authors.forename: Caroline
authors.initials: C
authors.lastname: Haglund
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.forename: Lars
authors.initials: L
authors.lastname: Bohlin
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
authors.forename: Linda
authors.initials: L
authors.lastname: Rickardson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D044004:Xanthones; C052659:gambogic acid; D046988:Proteasome Endopeptidase Complex