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

Yonas Getachew, Frank A. Cusimano, Purva Gopal, Scott A. Reisman, Jerry W. Shay

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 (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.

Original languageEnglish (US)
Article numberkfv213
Pages (from-to)111-120
Number of pages10
JournalToxicological Sciences
Volume149
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

Liver Cirrhosis
Liver
Hepatocellular Carcinoma
Fibrosis
Theoretical Models
Survival
Wounds and Injuries
Bilirubin
Ascites
Genes
Serum
Carbon Tetrachloride
Hydroxyproline
Transforming Growth Factors
Nutrition
Interleukin-10
Muscle
Liver Neoplasms
Actins
Anti-Inflammatory Agents

Keywords

  • Antiinflammatory
  • Antioxidant
  • Carbon tetrachloride
  • CDDO-EA
  • Cirrhosis
  • End stage liver disease
  • Hepatocellular carcinoma
  • Liver fibrosis
  • RTA 405
  • Triterpenoid

ASJC Scopus subject areas

  • Toxicology

Cite this

@article{f27d2fff41bd497bb4135c96a2a8c1c9,
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 (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.",
keywords = "Antiinflammatory, Antioxidant, Carbon tetrachloride, CDDO-EA, Cirrhosis, End stage liver disease, Hepatocellular carcinoma, Liver fibrosis, RTA 405, Triterpenoid",
author = "Yonas Getachew and Cusimano, {Frank A.} and Purva Gopal and Reisman, {Scott A.} and Shay, {Jerry W.}",
year = "2016",
month = "1",
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doi = "10.1093/toxsci/kfv213",
language = "English (US)",
volume = "149",
pages = "111--120",
journal = "Toxicological Sciences",
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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.

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 - Carbon tetrachloride

KW - CDDO-EA

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

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VL - 149

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JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

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