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.