Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator-activated receptor {gamma} agonists in colon cancer cells.
نویسندگان
چکیده
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.
منابع مشابه
اثرایمونوتراپیوتیک آل- ترانس رتینوئیک اسید بر دیابت تیپ 1 در موش و تاثیر آن بر بیان ژن (peroxisome proliferator- activated receptor gamma (PPARγ
Background: All-trans retinoic acid (ATRA) has a variety of biological activities, including immunomodulatory action in a number of inflammatory and autoimmune diseases. The purpose of this study was to investigate the effects of all-trans retinoic acid on the treatment of autoimmune diabetes in mice and its effects on expressions of Peroxisome Proliferator-Activated Receptor gamma (PPARγ...
متن کاملMethyl 2-cyano-3,11-dioxo-18 beta-olean-1,12-dien-30-oate is a peroxisome proliferator-activated receptor-gamma agonist that induces receptor-independent apoptosis in LNCaP prostate cancer cells.
Methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-diene-30-oate (beta-CDODA-Me) is a synthetic analog of the naturally occurring triterpenoid glycyrrhetinic acid, which contains a 2-cyano substituent in the A-ring. beta-CDODA-Me was a potent inhibitor of LNCaP prostate cancer cell growth (IC(50) approximately 1 muM) and activated peroxisome proliferator-activated receptor gamma (PPARgamma), whereas a...
متن کاملRole of peroxisome proliferator-activated receptor alpha and gamma in antiangiogenic effect of pomegranate peel extract
Objective(s): Herbal medicines are promising cancer preventive candidates. It has been shown that Punica granatum L. could inhibit angiogenesis and tumor invasion. In this study, we investigated whether the anti-angiogenic effect of pomegranate peel extract (PPE) is partly attributable to Peroxisome proliferator-activated receptors (PPARs) activation in the Human Umbilical Vein Endothelial Cell...
متن کاملCompare the Effect of Eicosapentaenoic Acid and Oxidized Low-Density Lipoprotein on the Expression of CD36 and Peroxisome Proliferator-Activated Receptor Gamma
Background: There is evidence that CD36 promotes foam cell formation through internalizing oxidized LDL (ox-LDL) into macrophages therefore, it plays a key role in pathogenesis of atherosclerosis. In addition, CD36 expression seems to be mediated by nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ). The aim of the present study was to evaluate and compare the effect of ...
متن کاملAssociation of Metformin Pharmacogenetic with a Single Amino Acid Alteration in Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Genein Patients with Polycystic Ovary Syndrome
Introduction: Polycystic ovarian syndrome (PCOS) is known as a metabolic, reproductive and ovarian degeneration disorder. Pro12 Ala mutation in peroxisome proliferator-activated receptor gamma (PPARγ) gene as a transcription factor is linked to disorder of glucose and infertility. In the patients with type 2 diabetes and polycystic ovary syndrome, metformin is the recommended first-line treatme...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Molecular cancer therapeutics
دوره 6 5 شماره
صفحات -
تاریخ انتشار 2007