title: Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator-activated receptor {gamma} agonists in colon cancer cells.
abstract: Glycyrrhizin, a pentacyclic triterpene glycoside, is the major phytochemical in licorice. This compound and its hydrolysis product glycyrrhetinic acid have been associated with the multiple therapeutic properties of licorice extracts. We have investigated the effects of 2-cyano substituted analogues of glycyrrhetinic acid on their cytotoxicities and activity as selective peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate (beta-CDODA-Me) and methyl 2-cyano-3,11-dioxo-18alpha-olean-1,12-dien-30-oate (alpha-CDODA-Me) were more cytotoxic to colon cancer cells than their des-cyano analogues and introduction of the 2-cyano group into the pentacyclic ring system was necessary for the PPARgamma agonist activity of alpha-CDODA-Me and beta-CDODA-Me isomers. However, in mammalian two-hybrid assays, both compounds differentially induced interactions of PPARgamma with coactivators, suggesting that these isomers, which differ only in the stereochemistry at C18 which affects conformation of the E-ring, are selective receptor modulators. This selectivity in colon cancer cells was shown for the induction of two proapoptotic proteins, namely caveolin-1 and the tumor-suppressor gene Krüppel-like factor-4 (KLF-4). beta-CDODA-Me but not alpha-CDODA-Me induced caveolin-1 in SW480 colon cancer cells, whereas caveolin-1 was induced by both compounds in HT-29 and HCT-15 colon cancer cells. The CDODA-Me isomers induced KLF-4 mRNA levels in HT-29 and SW480 cells but had minimal effects on KLF-4 expression in HCT-15 cells. These induced responses were inhibited by cotreatment with a PPARgamma antagonist. This shows for the first time that PPARgamma agonists derived from glycyrrhetinic acid induced cell-dependent caveolin-1 and KLF-4 expression through receptor-dependent pathways.
authors.affiliation: Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas, TX 77843-4466, USA.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Chintharlapalli
authors.forename: Sabitha
authors.initials: S
authors.lastname: Papineni
authors.forename: Indira
authors.initials: I
authors.lastname: Jutooru
authors.forename: Alan
authors.initials: A
authors.lastname: McAlees
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000737:chemistry*; D006035:Glycyrrhiza; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008024:Ligands; D008956:Models, Chemical; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors; D010957:Plasmids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020798:Two-Hybrid System Techniques
chemical_list: D000970:Antineoplastic Agents; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D008024:Ligands; D047495:PPAR gamma; D012333:RNA, Messenger; D006034:Glycyrrhetinic Acid