This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chintharlapalli, S. Articles by Safe, S. Search for Related Content PubMed PubMed Citation Articles by Chintharlapalli, S. Articles by Safe, S.

Research Articles: Therapeutics, Targets, and Development

Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator–activated receptor agonists in colon cancer cells

¹ Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas; ² Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas; and ³ Wellington Laboratories, Guelph, Ontario, Canada

Requests for reprints: Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, Veterinary Research Building 409, College Station, TX 77843-4466. Phone: 979-845-5988; Fax: 979-862-4929. E-mail: ssafe{at}cvm.tamu.edu

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 (PPAR) agonists. Methyl 2-cyano-3,11-dioxo-18ß-olean-1,12-dien-30-oate (ß-CDODA-Me) and methyl 2-cyano-3,11-dioxo-18-olean-1,12-dien-30-oate (-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 PPAR agonist activity of -CDODA-Me and ß-CDODA-Me isomers. However, in mammalian two-hybrid assays, both compounds differentially induced interactions of PPAR 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). ß-CDODA-Me but not -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 PPAR antagonist. This shows for the first time that PPAR agonists derived from glycyrrhetinic acid induced cell-dependent caveolin-1 and KLF-4 expression through receptor-dependent pathways. [Mol Cancer Ther 2007;6(5):1588–98]

Grant support: NIH grants ES09106 and CA11233 and the Texas Agricultural Experiment Station.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: S. Chintharlapalli and S. Papineni contributed equally to this work.

Received 1/10/07; revised 3/ 7/07; accepted 3/29/07.

This article has been cited by other articles:

				T. D. Wiggin, M. Kretzler, S. Pennathur, K. A. Sullivan, F. C. Brosius, and E. L. Feldman Rosiglitazone Treatment Reduces Diabetic Neuropathy in Streptozotocin-Treated DBA/2J Mice Endocrinology, October 1, 2008; 149(10): 4928 - 4937. [Abstract] [Full Text] [PDF]

				S. D. Cho, S. Chintharlapalli, M. Abdelrahim, S. Papineni, S. Liu, J. Guo, P. Lei, A. Abudayyeh, and S. Safe 5,5'-Dibromo-bis(3'-indolyl)methane induces Kruppel-like factor 4 and p21 in colon cancer cells Mol. Cancer Ther., July 1, 2008; 7(7): 2109 - 2120. [Abstract] [Full Text] [PDF]

				S. Papineni, S. Chintharlapalli, and S. Safe Methyl 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 Mol. Pharmacol., February 1, 2008; 73(2): 553 - 565. [Abstract] [Full Text] [PDF]