Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma

Table 2 Studies on the effect of angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers in diethylnitrosamine-induced hepatocellular carcinoma animal models

	Animal model	Treatment	Results	Comments
Saber et al[25]	DEN-induced HCC in mice	I. Sorafenib	Both treatments improved liver histology; II. reduced α-feto-protein and VEGF level	Inhibition of proliferation by involvement of NFкB pathway and cyclin D1
		vs
		II. ACEIs or ARBs
Saber et al[26]	DEN-induced HCC in mice	1 Sorafenib	ACE-Is and ARBs monotherapy or plus sorafenib improved liver histology with regression to grade 1, almost restoration of lobular architecture	No survival improvement
		2 ACE-I ± Sorafenib		No additional effect when combination therapy was used
		3 ARB ± Sorafenib
Nasr et al[27]	DEN-induced HCC in mice	Leflunomide Perindopril Curcumin	All drugs abrogated: hepatic microvessel density, elevated VEGF; only curcumin reduced HIF-1α. Nodules reduced or absent	Combination of these agents: further inhibited neovascularization
Mansour et al[29]	DEN + carbon tetra-chloride in rats	ACE-I ARBs	Significant reduction of tumor markers and hepatic growth factors	Liver histology amelioration correlated with VEGF, CD31 and FGF
Yanase et al[30]	DEN-treated rats	combined effect of ACE-I and 5-fluorouracil	Inhibition of HCC growth, neovascularization (VEGF and CD31+ vessels suppression), and marked increase of apoptosis	In vitro studies on EC tubular formation confirm the anti-angiogenetic effect
	Male BALB/c mice with injections of BNL-HCC cells.
Yoshiji et al[31]	DEN-treated mice	Vit. K and ACE-I used singularly or in combination	Inhibitory effects by each compound on hepato-carcinogenesis, more potent when used in combination	Increased apoptosis in the tumor, w/o any effect on tumor cell proliferation; CD31 mRNA suppression
	Male BALB/c mice with injections of BNL-HCC cells
Yoshiji et al[32]	DEN-treated rats and human HCC cell lines	Vit. K or ACE-I alone or in combination	Chemopreventive effect on pre-neoplastic foci formation by single compounds, more potent when combined.	Inhibition of endothelial cell proliferation and tubular formation; reduction of CD31 mRNA expression.
Yoshiji et al[33]	DEN-treated rats	Interferon, ACE-I used singularly or in combination	IFN or PE, when used singularly, significantly attenuated, in combination nearly abolished HCC	CD31 and VEGF mRNA expression were reduced; apoptosis was also reduced; no change of cell proliferation
Yoshiji et al[34]	DEN-treated rats	Perindopril (ACE-I)	Inhibition of neo-vascularization and VEGF expression	Suppression of VEGF-induced tubular formation; no effect on endothelial cell proliferation in vitro
	Endothelial cells in vitro

ACE-Is: Angiotensin-converting enzyme inhibitors; ARBs: Angiotensin II type 1 receptor blockers; Vit.: Vitamine; DEN: Diethylnitrosamine; HCC: Hepatocellular carcinoma; VEGF: Vascular endothelial growth factor; HIF: Hypoxia-inducible factor.