Pioglitazone Reduces Hepatocellular Carcinoma Development in Two Rodent Models of Cirrhosis

Shen Li, Sarani Ghoshal, Mozhdeh Sojoodi, Gunisha Arora, Ricard Masia, Derek J. Erstad, Michael Lanuti, Yujin Hoshida, Thomas F. Baumert, Kenneth K. Tanabe, Bryan C. Fuchs

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide due to the lack of effective treatments. Chemoprevention in high-risk patients is a promising, alternative strategy. In this study, pioglitazone was investigated for its ability to prevent hepatocarcinogenesis in two rodent models of cirrhosis. Methods: In the first model, male Wistar rats were given repeated, low-dose injections of diethylnitrosamine (DEN) to accurately recapitulate the progression of fibrosis to cirrhosis and HCC. In the second model, a single dose of DEN was administered to male C57Bl/6 pups at day fifteen followed by administration of a choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) at week six for 24 weeks. Pioglitazone treatment started at the first signs of fibrosis in both models. Results: Pioglitazone effectively reduced fibrosis progression and HCC development in both models. Gross tumor nodules were significantly reduced after pioglitazone treatment (7.4 ± 1.6 vs. 16.6 ± 2.6 in the rat DEN model and 5.86 ± 1.82 vs. 13.2 ± 1.25 in the mouse DEN+CDAHFD model). In both models, pioglitazone reduced the activation of mitogen-activated protein kinase (MAPK) and upregulated the hepato-protective AMP-activated protein kinase (AMPK) pathway via increasing circulating adiponectin production. Conclusion: Pioglitazone is an effective agent for chemoprevention in rodents and could be repurposed as a multi-targeted drug for delaying liver fibrosis and hepatocarcinogenesis.

Original languageEnglish (US)
Pages (from-to)101-111
Number of pages11
JournalJournal of Gastrointestinal Surgery
Volume23
Issue number1
DOIs
StatePublished - Jan 15 2019

Fingerprint

pioglitazone
Diethylnitrosamine
Hepatocellular Carcinoma
Rodentia
Fibrosis
Chemoprevention
High Fat Diet
Choline
Amino Acids
AMP-Activated Protein Kinases
Adiponectin
Mitogen-Activated Protein Kinases
Liver Cirrhosis
Wistar Rats
Neoplasms
Therapeutics

Keywords

  • AMPK
  • Chemoprevention
  • Fibrosis
  • HCC
  • NASH
  • PPARγ

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

Cite this

Li, S., Ghoshal, S., Sojoodi, M., Arora, G., Masia, R., Erstad, D. J., ... Fuchs, B. C. (2019). Pioglitazone Reduces Hepatocellular Carcinoma Development in Two Rodent Models of Cirrhosis. Journal of Gastrointestinal Surgery, 23(1), 101-111. https://doi.org/10.1007/s11605-018-4004-6

Pioglitazone Reduces Hepatocellular Carcinoma Development in Two Rodent Models of Cirrhosis. / Li, Shen; Ghoshal, Sarani; Sojoodi, Mozhdeh; Arora, Gunisha; Masia, Ricard; Erstad, Derek J.; Lanuti, Michael; Hoshida, Yujin; Baumert, Thomas F.; Tanabe, Kenneth K.; Fuchs, Bryan C.

In: Journal of Gastrointestinal Surgery, Vol. 23, No. 1, 15.01.2019, p. 101-111.

Research output: Contribution to journalArticle

Li, S, Ghoshal, S, Sojoodi, M, Arora, G, Masia, R, Erstad, DJ, Lanuti, M, Hoshida, Y, Baumert, TF, Tanabe, KK & Fuchs, BC 2019, 'Pioglitazone Reduces Hepatocellular Carcinoma Development in Two Rodent Models of Cirrhosis', Journal of Gastrointestinal Surgery, vol. 23, no. 1, pp. 101-111. https://doi.org/10.1007/s11605-018-4004-6
Li, Shen ; Ghoshal, Sarani ; Sojoodi, Mozhdeh ; Arora, Gunisha ; Masia, Ricard ; Erstad, Derek J. ; Lanuti, Michael ; Hoshida, Yujin ; Baumert, Thomas F. ; Tanabe, Kenneth K. ; Fuchs, Bryan C. / Pioglitazone Reduces Hepatocellular Carcinoma Development in Two Rodent Models of Cirrhosis. In: Journal of Gastrointestinal Surgery. 2019 ; Vol. 23, No. 1. pp. 101-111.
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abstract = "Background: Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide due to the lack of effective treatments. Chemoprevention in high-risk patients is a promising, alternative strategy. In this study, pioglitazone was investigated for its ability to prevent hepatocarcinogenesis in two rodent models of cirrhosis. Methods: In the first model, male Wistar rats were given repeated, low-dose injections of diethylnitrosamine (DEN) to accurately recapitulate the progression of fibrosis to cirrhosis and HCC. In the second model, a single dose of DEN was administered to male C57Bl/6 pups at day fifteen followed by administration of a choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) at week six for 24 weeks. Pioglitazone treatment started at the first signs of fibrosis in both models. Results: Pioglitazone effectively reduced fibrosis progression and HCC development in both models. Gross tumor nodules were significantly reduced after pioglitazone treatment (7.4 ± 1.6 vs. 16.6 ± 2.6 in the rat DEN model and 5.86 ± 1.82 vs. 13.2 ± 1.25 in the mouse DEN+CDAHFD model). In both models, pioglitazone reduced the activation of mitogen-activated protein kinase (MAPK) and upregulated the hepato-protective AMP-activated protein kinase (AMPK) pathway via increasing circulating adiponectin production. Conclusion: Pioglitazone is an effective agent for chemoprevention in rodents and could be repurposed as a multi-targeted drug for delaying liver fibrosis and hepatocarcinogenesis.",
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AU - Li, Shen

AU - Ghoshal, Sarani

AU - Sojoodi, Mozhdeh

AU - Arora, Gunisha

AU - Masia, Ricard

AU - Erstad, Derek J.

AU - Lanuti, Michael

AU - Hoshida, Yujin

AU - Baumert, Thomas F.

AU - Tanabe, Kenneth K.

AU - Fuchs, Bryan C.

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N2 - Background: Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide due to the lack of effective treatments. Chemoprevention in high-risk patients is a promising, alternative strategy. In this study, pioglitazone was investigated for its ability to prevent hepatocarcinogenesis in two rodent models of cirrhosis. Methods: In the first model, male Wistar rats were given repeated, low-dose injections of diethylnitrosamine (DEN) to accurately recapitulate the progression of fibrosis to cirrhosis and HCC. In the second model, a single dose of DEN was administered to male C57Bl/6 pups at day fifteen followed by administration of a choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) at week six for 24 weeks. Pioglitazone treatment started at the first signs of fibrosis in both models. Results: Pioglitazone effectively reduced fibrosis progression and HCC development in both models. Gross tumor nodules were significantly reduced after pioglitazone treatment (7.4 ± 1.6 vs. 16.6 ± 2.6 in the rat DEN model and 5.86 ± 1.82 vs. 13.2 ± 1.25 in the mouse DEN+CDAHFD model). In both models, pioglitazone reduced the activation of mitogen-activated protein kinase (MAPK) and upregulated the hepato-protective AMP-activated protein kinase (AMPK) pathway via increasing circulating adiponectin production. Conclusion: Pioglitazone is an effective agent for chemoprevention in rodents and could be repurposed as a multi-targeted drug for delaying liver fibrosis and hepatocarcinogenesis.

AB - Background: Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide due to the lack of effective treatments. Chemoprevention in high-risk patients is a promising, alternative strategy. In this study, pioglitazone was investigated for its ability to prevent hepatocarcinogenesis in two rodent models of cirrhosis. Methods: In the first model, male Wistar rats were given repeated, low-dose injections of diethylnitrosamine (DEN) to accurately recapitulate the progression of fibrosis to cirrhosis and HCC. In the second model, a single dose of DEN was administered to male C57Bl/6 pups at day fifteen followed by administration of a choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) at week six for 24 weeks. Pioglitazone treatment started at the first signs of fibrosis in both models. Results: Pioglitazone effectively reduced fibrosis progression and HCC development in both models. Gross tumor nodules were significantly reduced after pioglitazone treatment (7.4 ± 1.6 vs. 16.6 ± 2.6 in the rat DEN model and 5.86 ± 1.82 vs. 13.2 ± 1.25 in the mouse DEN+CDAHFD model). In both models, pioglitazone reduced the activation of mitogen-activated protein kinase (MAPK) and upregulated the hepato-protective AMP-activated protein kinase (AMPK) pathway via increasing circulating adiponectin production. Conclusion: Pioglitazone is an effective agent for chemoprevention in rodents and could be repurposed as a multi-targeted drug for delaying liver fibrosis and hepatocarcinogenesis.

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