Journal of Gastroenterology

, Volume 49, Issue 10, pp 1421–1429 | Cite as

Combination of sorafenib and angiotensin-II receptor blocker attenuates preneoplastic lesion development in a non-diabetic rat model of steatohepatitis

  • Hitoshi YoshijiEmail author
  • Ryuichi Noguchi
  • Tadashi Namisaki
  • Kei Moriya
  • Mitsuteru Kitade
  • Yosuke Aihara
  • Akitoshi Douhara
  • Hideto Kawaratani
  • Norihisa Nishimura
  • Hiroshi Fukui
Original Article—Liver, Pancreas, and Biliary Tract



Given the well-documented adverse side effects of sorafenib, many sorafenib-treated patients may need the reduced initial dose of the compound, and an alternative sorafenib-based therapy, which exerts similar clinical benefit, is anticipated. An angiostatic therapy with sorafenib is considered one of the promising approaches for chemoprevention of hepatocellular carcinoma. The aim of the current study was to elucidate the combination effect of low dose of sorafenib and angiotensin-II receptor blocker (ARB) on hepatocarcinogenesis, especially in conjunction with angiogenesis.


The chemopreventive effect on the development of liver preneoplastic lesions, angiogenesis, and several indices was elucidated in rats. We also performed several sets of in vitro experiments to examine the mechanisms involved.


Using a non-diabetic rat model of steatohepatitis with choline deficient l-amino acid-defined diet, sorafenib demonstrated marked inhibition of preneoplastic lesions in a dose dependent manner. Combined treatment with ARB (losartan) at a clinically comparable dose and half dose of sorafenib resulted in the inhibitory effect equivalent to that of common dose of sorafenib along with suppression of hepatic neovascularization and potent angiogenic factor, vascular endothelial growth factor. Furthermore, similar combined inhibitory outcomes were observed in several sets of in vitro studies.


Since the combinatorial treatment using low doses of sorafenib and ARB could sufficiently induce inhibitory effect on the development of preneoplastic lesions at the magnitude similar to the conventional dose of sorafenib, this regimen may provide new strategy for patients intolerant of the usual dose of sorafenib in the future.


Angiogenesis Angiotensin-II Non-alcoholic steatohepatitis Hepatocarcinogenesis Sorafenib 


Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Japan 2013

Authors and Affiliations

  • Hitoshi Yoshiji
    • 1
    Email author
  • Ryuichi Noguchi
    • 1
  • Tadashi Namisaki
    • 1
  • Kei Moriya
    • 1
  • Mitsuteru Kitade
    • 1
  • Yosuke Aihara
    • 1
  • Akitoshi Douhara
    • 1
  • Hideto Kawaratani
    • 1
  • Norihisa Nishimura
    • 1
  • Hiroshi Fukui
    • 1
  1. 1.Third Department of Internal MedicineNara Medical UniversityKashiharaJapan

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