title: The Synthetic Triterpenoid RTA 405 (CDDO-EA) Halts Progression of Liver Fibrosis and Reduces Hepatocellular Carcinoma Size Resulting in Increased Survival in an Experimental Model of Chronic Liver Injury.
abstract: 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.
authors.affiliation: *Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; yonas.getachew@utsouthwestern.edu.
authors.forename: Yonas
authors.initials: Y
authors.lastname: Getachew
authors.affiliation: *Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center;
authors.forename: Frank A
authors.initials: FA
authors.lastname: Cusimano
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center;
authors.forename: Purva
authors.initials: P
authors.lastname: Gopal
authors.affiliation: Early Development, Reata Pharmaceutical, Inc., 2801 Gateway Dr. Ste 150, Dallas, Texas 75063; and.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Reisman
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9151.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D045744:Cell Line, Tumor; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D018450:Disease Progression; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: C518860:2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid ethyl amide; D016207:Cytokines; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009828:Oleanolic Acid; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1
keywords: CDDO-EA; RTA 405; and end stage liver disease; antiinflammatory; antioxidant; carbon tetrachloride; cirrhosis; hepatocellular carcinoma; liver fibrosis; triterpenoid