Key result
Administration of perindopril, fosinopril, or losartan improved liver histology but did not significantly improve overall survival in mice with diethylnitrosamine-induced hepatocellular carcinoma.
Why the study?
Does renin-angiotensin system inhibition improve overall survival in mice with diethylnitrosamine-induced hepatocellular carcinoma?
Does renin-angiotensin system inhibition improve overall survival in mice with diethylnitrosamine-induced hepatocellular carcinoma?
p-value: p=>0.05
In a mouse model of DEN-induced HCC, RAS inhibition improved liver histology but did not improve overall survival, suggesting this specific model is inappropriate for mortality assessments.
Should not inform clinical RAS inhibitor use in HCC; leaves open whether this DEN model suits survival assessments in future preclinical work.
BACKGROUND: Preclinical studies have demonstrated that renin-angiotensin system (RAS) signalling has strong tumour-promoting effects and RAS inhibition was associated with improvement in the overall survival in some cancer types including hepatocellular carcinoma (HCC). OBJECTIVE: We aimed to investigate the effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-II-receptor blockers (ARBs) on the survival of mice with diethylnitrosamine (DEN) induced HCC. METHODS: HCC was induced by weekly i.p. administration of DEN. Mice were treated with sorafenib (SO) (30 mg/kg), perindopril (PE) (1 mg/kg), fosinopril (FO) (2 mg/kg), losartan (LO) (10 mg/kg), PE (1 mg/kg) + SO (30 mg/kg), FO (2 mg/kg) + SO (30 mg/kg), or LO (10 mg/kg) + SO (30 mg/kg). Survival analysis was done using the Kaplan-Meier method, and the log-rank test was used for assessing the significance of difference between groups. RESULTS: The administration of PE, FO and LO as monotherapy or as combined with SO resulted in marked improvement in the liver histologic picture with no impact on overall survival of mice. CONCLUSION: Interfering the RAS either through the inhibition of ACE or the blockade of angiotensin II type 1 (AT1) receptors has similar effects on the liver of DEN-induced HCC mice and is not associated with longer survival due to detrimental effects of DEN on other organs. Hence, repetitive administration of DEN in such models of HCC is not suitable for mortality assessment studies.
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Saber et al. (2018) studied Hepatocellular carcinoma (n=270). Renin-angiotensin system inhibitors (perindopril, fosinopril, losartan) with or without sorafenib vs. Diethylnitrosamine alone or sorafenib alone was evaluated on Overall survival (median survival time) (p=>0.05). Administration of perindopril, fosinopril, or losartan improved liver histology but did not significantly improve overall survival in mice with diethylnitrosamine-induced hepatocellular carcinoma.
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