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

• Published in: Toxicology letters 2018-10, Vol.295, p.32-40
• Main Authors: Saber, Sameh, Mahmoud, Amr A.A., Goda, Reham, Helal, Noha S., El-ahwany, Eman, Abdelghany, Rasha H.
• Format: Article
• Language: English
• Subjects: Diethylnitrosamine; Hepatocellular carcinoma; Renin-angiotensin system; Sorafenib
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2018.05.036

The proposed mechanism of action for sorafenib, perindopril, fosinopril and losartan in interfering with NFκB pathway. Ang, angiotensin; AT1R, angiotensin II type 1 receptor; DAG, diacyl glycerol; ERK, extracellular signal-regulated kinase; FO, fosinopril; IkB, inhibitory kappa B protein; IKK, IκB kinase; IP3, inositol triphosphate; LO, losartan; MEK, mitogen-activated protein kinase kinase; MMP-2, matrix metalloproteinase 2; NFkB, nuclear transcription factor kappa B; PDGFRβ, platelet derived growth factor receptor beta; PE, perindopril; PLC, phospholipase C; SO, sorafenib; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. [Display omitted] •RAS inhibitors inhibited phosphorylation induced activation of NFкB proteins.•RAS inhibitors demonstrated anti-angiogenic and anti-proliferative properties.•RAS inhibitors resulted in improved liver function and histology in experimental HCC. 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.