Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of death among cirrhotic patients, for which chemopreventive strategies are lacking. Recently, we developed a simple human cell-based system modeling a clinical prognostic liver signature (PLS) predicting liver disease progression and HCC risk. In a previous study, we applied our cell-based system for drug discovery and identified captopril, an approved angiotensin converting enzyme (ACE) inhibitor, as a candidate compound for HCC chemoprevention. Here, we explored ACE as a therapeutic target for HCC chemoprevention. Captopril reduced liver fibrosis and effectively prevented liver disease progression toward HCC development in a diethylnitrosamine (DEN) rat cirrhosis model and a diet-based rat model for nonalcoholic steatohepatitis–induced (NASH-induced) hepatocarcinogenesis. RNA-Seq analysis of cirrhotic rat liver tissues uncovered that captopril suppressed the expression of pathways mediating fibrogenesis, inflammation, and carcinogenesis, including epidermal growth factor receptor (EGFR) signaling. Mechanistic data in liver disease models uncovered a cross-activation of the EGFR pathway by angiotensin. Corroborating the clinical translatability of the approach, captopril significantly reversed the HCC high-risk status of the PLS in liver tissues of patients with advanced fibrosis. Captopril effectively prevents fibrotic liver disease progression toward HCC development in preclinical models and is a generic and safe candidate drug for HCC chemoprevention.

Network pharmacology and in vitro experiments-based strategy to investigate the mechanisms of KangXianYiAi formula for hepatitis B virus-related hepatocellular carcinoma

“…The HBx promotes cell proliferation by disturbing the cross-talk between PTEN and miR-181a in HBV-related hepato-carcinogenesis ( Tian et al, 2017 ). EGFR ( Crouchet et al, 2022 ) and HDAC1 ( Rivas et al, 2021 ) have a role in promoting hepatocarcinogenesis. The upregulation of EGFR promotes the progression of HCC and leads to sorafenib resistance ( Pang et al, 2019 ).…”

Cardiometabolic risk factors in MASLD patients with HCC: the other side of the coin

“…The use of antihypertensive drugs, which include angiotensin-converting enzyme inhibitors (ACEi), calcium channel blockers (CCBs), beta-adrenoceptor blockers (BBs), angiotensin receptor blockers (ARBs) and thiazide diuretics, is a critical component in MASLD management, since hypertension showed an independent association with HCC risk and poor prognosis ( 117 ). Nonetheless, it is still unclear whether and how antihypertensive drugs may modify the risk of HCC or may limit the efficacy of anti-cancer therapies ( 118 , 119 ). For instance, captopril, an ACEi, reduced hepatic fibrosis and prevented progression towards HCC development in murine models of liver cancer ( 119 ).…”

Hepatocellular Carcinoma Chemoprevention with Generic Agents

“…8 An ACEI, captopril, suppresses fibrogenic and inflammatory pathways such as EGFR signaling, reverses high-risk PLS, and reduces HCC nodules in chemical- and diet-induced rat models of NAFLD-driven HCC. 109 A small meta-analysis of cohort studies showed that use of ACEIs/ARBs was associated with lower HCC risk (RR, 0.51; 95% CI, 0.44–0.60). 110 In a subsequent nested case–control study from Korea, use of ARBs at 30 cDDD or higher showed inverse association with presence of HCC (aOR, 0.65; 95% CI, 0.43–0.97).…”