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

Abstract

BACKGROUND Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs. AIM To elucidate the role of ARBs and ACE-Is in HCC. METHODS We performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma; moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro . Abstracts, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals. RESULTS Thirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs. CONCLUSION In humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.

Renin-angiotensin inhibitors were associated with improving outcomes of hepatocellular carcinoma with primary hypertension after hepatectomy

“…Lungs are the main extrahepatic organs of hematogenous metastasis of HCC. In vivo, Ang II can promote pulmonary metastasis of tumors by activating adhesion molecules in vascular endothelial cells and inhibiting tumor angiogenesis, and these effects can be attenuated by RASIs (32)(33)(34). In our study, extrahepatic metastases of HCC were observed in 23 patients, and pulmonary metastasis occurred in 21 patients.…”

“…Obviously, RASI was a kind of cardiovascular drugs instead of anticancer drugs preferentially and it might control cancer by remolding the tumor cells or reforming the tumor microenvironment instead of killing tumors directly (49). In previous clinical studies, it seemed that RASI significantly suppressed the cumulative HCC recurrence, and without prolonging patient survival (34). Probably, the beneficial effects on OS of RASI in HCC treatment could be more visible when the tumor burden was eliminated (curative resection or radiofrequency ablation) or it was combined with anticancer drugs (19,20).…”

Antihypertensive Drugs and the Risk of Cancer: A Nationwide Cohort Study

“…From site-specific analysis, we speculated that the reduced cancer risk associated with ARB use is driven by a decrease in hepatic cancer and gastric cancer, although our analysis per type of cancer should be interpreted with caution and warrants further investigation. Theoretically, neoangiogenesis is one of the key pathogenic mechanisms in hepatic cancer, and modulation of the renin-angiotensin-aldosterone system seems to be a possible anti-tumor mechanism of the anti-angiogenic and anti-fibrogenic activity of ARBs [ 31 ]. AT1R is upregulated in human gastric cancer and may be involved in the progression of gastric cancer.…”

The Relationship Between Anti-Hypertensive Drugs and Cancer: Anxiety to be Resolved in Urgent

“…In the same vein, the systematic reviews conducted by Barone et al (Barone et al, 2019) and Asgharzadeh et al (Asgharzadeh et al, 2020b) have shown that RAS inhibitors have beneficial effects on hepatocellular carcinoma. Thiele et al (Thiele et al, 2015) conducted a meta-analysis of RCTs and found that nonselective BBs might prevent the risk of liver cancer in patients with cirrhosis (risk difference −0.026; 95% CI-0.052 to −0.001).…”