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

Table 3 Experimental studies on the effect of angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers in different hepatocellular carcinoma animal models and in hepatocellular carcinoma cell lines

	Model	Treatment	Results	Comments
Fan et al[35]	1 Tumor cell lines	Candesartan	Angiotensin II up-regulated AT1R and promoted production of VEGF in vitro. Candesartan reversed this process and downregulated the expression of VEGF-A in tumor xenografts	AT1R expression was associated to angiogenic potential in HCC human tissues
	2 BALB/c nude mice with injections of HCC cell lines
	3 Human HCC specimens
Du et al[36]	1 Tumor cell lines	AT2R over- expression by AT2R recombinant adenoviral vector	Overexpression of AT2R in transduced HCC cell lines produced apoptosis and inhibited cell proliferation. Higher AT2R expression could increase the growth of HCC and the prolifera-tion of HCC cells in vivo	A moderate expression of AT2R could increase the growth of HCC and the proliferation of HCC cells in vivo. AT2R mechanisms remain to be elucidated
	2 BALB/c nude mice with intra-liver injections of human HCC cells
Noguchi et al[37]	BALB/c mice injected with HCC cell lines	ACE-I and interferon-beta	Combination therapy was effective even on established tumors. Suppression of VEGF and endothelial cell proliferation and tubular formation, increase of apoptosis;	No effect on HCC cell proliferation.
Yoshiji et al[38]	BALB/c mice injected with HCC cell lines. Endothelial cell cultures	Retroviral tetracycline up-regulated VEGF gene expression and Perindopril (ACE-I)	Perindopril significantly attenuated VEGF-mediated tumor growth and neovascularization. In vitro, VEGF-induced endothelial cell migration inhibition	Suppression of VEGF
Yoshiji et al[39]	BALB/c mice injected with HCC cell lines. BNL CL2 cell line	Captopril Perindopril Temocapril Losartan Candesartan	Reduction of tubular formation and microvessel density in the tumor. Higher VEGF mRNA expression reduction and HCC growth inhibition by perindopril compared to temocapril and captopril. Neither candesartan nor losartan significantly inhibited the tumor development	ACE-Is suppressed the tumor development mainly by a mechanism which was independent from AT1-R blockage.
Tamaki et al[40]	Male Wistar rats receiving modified choline-deficient low-methionine diet	Telmisartan	No HCC in telmisartan group vs 54.6% of HCC in control group. Telmisartan inhibited the dietary-induced up-regulation of VEGF, TGF-β1, CTGF, HIF1α and TNF-α mRNA levels	Telmisartan may prevent hepatocarcinogenesis through the inhibition of hepatic angiogenesis
Noguchi et al[41]	Male Fisher-344 rats receiving modified choline-deficient low-methionine diet	Perindopril Eplerenone (selective aldosterone blocker) Aldosterone	Significant inhibitory effects on the GST-P positive pre-neoplastic lesion development; reduction of VEGF expression tubule formation and neovascularization	Combination of Perindopril + Eplerenone exerted a stronger suppression than single treatment
Yoshiji et al[42]	Male OLETF rats (spontaneous development of insulin resistance) treated with Diethylnitrosamine	branched-chain amino acids perindopril	Number/size of preneoplastic foci were significantly suppressed by treatment of both drugs suppression of CD31- and VEGF-mRNA	In vitro suppression of tubule formation, regardless of drug concentration
Oura et al[43]	Five human HCC cell lines (HepG2, HLF, HLE, HuH-7 and PLC/PRF/5)	Telmisartan	Only telmisartan reduced proliferation in most of cell lines. Promotion of apoptosis, Enhancement of bFGF reduction of p-ErbB3	Arrest of cell cycle in G1, and S phase. Effect is dose-dependent and may be mediated by induction of MPK/mTOR signaling.
		Valsartan
		Irbesartan
		Losartan
Santhekadur et al[44]	Hep3B and QGY-7703 cell lines	Losartan	SND1 increases AT1R level by augmenting AT1R mRNA stability; Losartan inhibited both cell migration and invasion	SND1 induces TGF-β expression through AT1R signaling
Cook et al[45]	H4-II-E-C3 rat hepatoma cells transfected with Ang II	Losartan Candesartan	Losartan inhibits Angiotensin II-induced proliferation	Both losartan and candesartan are equally effective in competing with Ang II/AT1 receptor interactions on the cell surface

Ang II: Angiotensin receptor; AT2R: Angiotensin II type 2 receptor; ACE-Is: Angiotensin-converting enzyme inhibitors; ARBs: Angiotensin II type 1 receptor blockers; HCC: Hepatocellular carcinoma; VEGF: Vascular endothelial growth factor; TNF: Tumor necrosis factor; TGF: Transforming growth factor; OLETF: Otsuka Long-Evans Tokushima Fatty.