Yonas Getachew1, Frank A Cusimano2, Purva Gopal3, Scott A Reisman4, Jerry W Shay5. 1. *Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; yonas.getachew@utsouthwestern.edu. 2. *Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; 3. Department of Pathology, University of Texas Southwestern Medical Center; 4. Early Development, Reata Pharmaceutical, Inc., 2801 Gateway Dr. Ste 150, Dallas, Texas 75063; and. 5. Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9151.
Abstract
UNLABELLED: Patients with cirrhosis have an increased risk of developing liver cancer and a higher rate of mortality. Cirrhosis currently has no known cure, and patients may benefit from new agents aimed at alleviating their complications and slowing down the rate of disease progression. Therefore, the effects of the orally bioavailable synthetic triterpenoid 2-cyano-3,12-dioxooleana- 1,9(11)-dien-28-oate-ethyl amide (CDDO-EA, RTA 405), which has potent antioxidative and antiinflammatory properties, was evaluated in a chronic carbon tetrachloride (CCl(4))-induced model of liver cirrhosis and hepatocellular carcinoma (HCC). Mice were injected with CCl(4) (to induce fibrosis and cirrhosis) or placebo biweekly for 12 weeks followed by CDDO-EA in the diet for 18 weeks with continued biweekly injections of CCl(4). Chronic CCl(4) administration resulted in cirrhosis, ascites, and HCC formation, associated with increased serum transforming growth factor-β1, hepatic hydroxyproline content, and increased serum bilirubin. CDDO-EA, whose administration commenced after establishment of liver fibrosis, decreased liver fibrosis progression, serum bilirubin, ascites, and HCC formation and markedly increased overall survival. CDDO-EA also attenuated -TNFα (tumor necrosis factor-α), α-SMA (alpha smooth muscle actin), augmented -IL-10 levels, and improved histologic and serologic markers of fibrosis. CONCLUSIONS: CDDO-EA mitigates the progression of liver fibrosis induced by chronic CCl(4) administration, which is associated with the induction of antifibrogenic genes and suppression of profibrogenic genes. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.
UNLABELLED: Patients with cirrhosis have an increased risk of developing liver cancer and a higher rate of mortality. Cirrhosis currently has no known cure, and patients may benefit from new agents aimed at alleviating their complications and slowing down the rate of disease progression. Therefore, the effects of the orally bioavailable synthetic triterpenoid 2-cyano-3,12-dioxooleana- 1,9(11)-dien-28-oate-ethyl amide (CDDO-EA, RTA 405), which has potent antioxidative and antiinflammatory properties, was evaluated in a chronic carbon tetrachloride (CCl(4))-induced model of liver cirrhosis and hepatocellular carcinoma (HCC). Mice were injected with CCl(4) (to induce fibrosis and cirrhosis) or placebo biweekly for 12 weeks followed by CDDO-EA in the diet for 18 weeks with continued biweekly injections of CCl(4). Chronic CCl(4) administration resulted in cirrhosis, ascites, and HCC formation, associated with increased serum transforming growth factor-β1, hepatic hydroxyproline content, and increased serum bilirubin. CDDO-EA, whose administration commenced after establishment of liver fibrosis, decreased liver fibrosis progression, serum bilirubin, ascites, and HCC formation and markedly increased overall survival. CDDO-EA also attenuated -TNFα (tumor necrosis factor-α), α-SMA (alpha smooth muscle actin), augmented -IL-10 levels, and improved histologic and serologic markers of fibrosis. CONCLUSIONS:CDDO-EA mitigates the progression of liver fibrosis induced by chronic CCl(4) administration, which is associated with the induction of antifibrogenic genes and suppression of profibrogenic genes. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.
Entities:
Keywords:
CDDO-EA; RTA 405; and end stage liver disease; antiinflammatory; antioxidant; carbon tetrachloride; cirrhosis; hepatocellular carcinoma; liver fibrosis; triterpenoid
Authors: Ekihiro Seki; Samuele De Minicis; Christoph H Osterreicher; Johannes Kluwe; Yosuke Osawa; David A Brenner; Robert F Schwabe Journal: Nat Med Date: 2007-10-21 Impact factor: 53.440
Authors: Dorrah Deeb; Xiaohua Gao; Hao Jiang; Branislava Janic; Ali S Arbab; Yon Rojanasakul; Scott A Dulchavsky; Subhash C Gautam Journal: Biochem Pharmacol Date: 2009-09-24 Impact factor: 5.858
Authors: Karen Liby; Darlene B Royce; Charlotte R Williams; Renee Risingsong; Mark M Yore; Tadashi Honda; Gordon W Gribble; Ethan Dmitrovsky; Thomas A Sporn; Michael B Sporn Journal: Cancer Res Date: 2007-03-15 Impact factor: 12.701
Authors: Tsutomu Fujii; Bryan C Fuchs; Suguru Yamada; Gregory Y Lauwers; Yakup Kulu; Jonathan M Goodwin; Michael Lanuti; Kenneth K Tanabe Journal: BMC Gastroenterol Date: 2010-07-09 Impact factor: 3.067
Authors: Danielle Brooks; Alexandra Zimmer; Lalage Wakefield; L Tiffany Lyle; Simone Difilippantonio; Fabio C Tucci; Stephane Illiano; Christina M Annunziata; Patricia S Steeg Journal: Oncotarget Date: 2018-05-04
Authors: James H Lewis; Michel Jadoul; Geoffrey A Block; Melanie P Chin; Deborah A Ferguson; Angie Goldsberry; Colin J Meyer; Megan O'Grady; Pablo E Pergola; Scott A Reisman; W Christian Wigley; Glenn M Chertow Journal: Clin Transl Sci Date: 2020-09-03 Impact factor: 4.689