Perindopril, fosinopril and losartan inhibited the progression of diethylnitrosamine-induced hepatocellular carcinoma in mice via the inactivation of nuclear transcription factor kappa-B

Toxicol Lett. 2018 Oct 1;295:32-40. doi: 10.1016/j.toxlet.2018.05.036. Epub 2018 May 31.

Abstract

Hepatocellular carcinoma (HCC) is a major global health problem. Therapeutic interventions of HCC are still limited because of its complicated molecular pathogenesis. Many reports showed that renin-angiotensin system (RAS) contributes to the development of different types of malignancies. Therefore, the present study aimed to examine the effect of RAS inhibition using perindopril (1 mg/kg), fosinopril (2 mg/kg), or losartan (10 mg/kg) on diethylnitrosamine-induced HCC compared to sorafenib (30 mg/kg). The administration of RAS inhibitors resulted in improved liver function and histologic picture with a reduction in AFP levels. These effects found to be mediated through inactivation of NFкB pathway by the inhibition of NFĸB p65 phosphorylation at the Ser536 residue and inhibition of the phosphorylation-induced degradation of NFĸBia. Consequently, expression levels of cyclin D1 mRNA were significantly lowered. In addition, NFкB-induced TNF-α and TGF-β1 levels were reduced leading to lower levels of MMP-2 and VEGF. We concluded that RAS inhibition either through inhibiting the ACE or the blockade of AT1R has the same therapeutic benefit and that the tissue affinity of the ACEIs has no impact on its anti-tumor activity. These results suggest that ACEIs and ARBs can serve as promising candidates for further clinical trials in the management of HCC.

Keywords: Diethylnitrosamine; Hepatocellular carcinoma; Renin-angiotensin system; Sorafenib.

Publication types

  • Comparative Study

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Diethylnitrosamine*
  • Fosinopril / pharmacology*
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / drug therapy*
  • Liver Neoplasms, Experimental / metabolism
  • Liver Neoplasms, Experimental / pathology
  • Losartan / pharmacology*
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • NF-KappaB Inhibitor alpha / metabolism
  • NF-kappa B / metabolism*
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Perindopril / pharmacology*
  • Phenylurea Compounds / pharmacology
  • Phosphorylation
  • Renin-Angiotensin System / drug effects*
  • Signal Transduction / drug effects
  • Sorafenib
  • Time Factors
  • Transcription Factor RelA / metabolism
  • Transforming Growth Factor beta1 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Antineoplastic Agents
  • Ccnd1 protein, mouse
  • NF-kappa B
  • NFKBIA protein, human
  • Phenylurea Compounds
  • Rela protein, mouse
  • Tgfb1 protein, mouse
  • Transcription Factor RelA
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Cyclin D1
  • NF-KappaB Inhibitor alpha
  • Niacinamide
  • Diethylnitrosamine
  • Sorafenib
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse
  • Losartan
  • Fosinopril
  • Perindopril