TY - JOUR
T1 - 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
AU - Getachew, Yonas
AU - Cusimano, Frank A.
AU - Gopal, Purva
AU - Reisman, Scott A.
AU - Shay, Jerry W.
N1 - Funding Information:
NIH 1K08DK085432 and the Jan and Henri Bromberg Chair in internal Medicine (Y.G.). The Southland Financial Corporation Distinguished Chair in Geriatric Research (J.W.S.). Part of this work was performed in laboratories constructedwith support from National Institute of Health grant C06 RR30414. Reata Pharmaceutical Inc., Irving TX provided CDDO-EA. The authors thank Dr. Donald L. Rockey (MUSC) for sharing his CCl4 animal protocol. Scott Reisman is an employee of Reata Pharmaceuticals, and Jerry Shay is a scientific advisor to Reata Pharmaceuticals.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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 (CCl4)-induced model of liver cirrhosis and hepatocellular carcinoma (HCC). Mice were injected with CCl4 (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 CCl4. Chronic CCl4 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 CCl4 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.
AB - 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 (CCl4)-induced model of liver cirrhosis and hepatocellular carcinoma (HCC). Mice were injected with CCl4 (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 CCl4. Chronic CCl4 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 CCl4 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.
KW - Antiinflammatory
KW - Antioxidant
KW - CDDO-EA
KW - Carbon tetrachloride
KW - Cirrhosis
KW - End stage liver disease
KW - Hepatocellular carcinoma
KW - Liver fibrosis
KW - RTA 405
KW - Triterpenoid
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U2 - 10.1093/toxsci/kfv213
DO - 10.1093/toxsci/kfv213
M3 - Article
C2 - 26443840
AN - SCOPUS:84960106625
SN - 1096-6080
VL - 149
SP - 111
EP - 120
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
M1 - kfv213
ER -