title: Combination of sorafenib and angiotensin-II receptor blocker attenuates preneoplastic lesion development in a non-diabetic rat model of steatohepatitis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan, yoshijih@naramed-u.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.forename: Kei
authors.initials: K
authors.lastname: Moriya
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Aihara
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Douhara
authors.forename: Hideto
authors.initials: H
authors.lastname: Kawaratani
authors.forename: Norihisa
authors.initials: N
authors.lastname: Nishimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D056945:Hep G2 Cells; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D019808:Losartan / Q000008:administration & dosage; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000473:pathology; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011230:Precancerous Conditions / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D011916:Rats, Inbred F344; D000077157:Sorafenib
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016588:Anticarcinogenic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D019808:Losartan