Abstract 2468: Selective aldosterone blocker inhibits murine hepatocellular carcinoma development via angiogenesis suppression

Abstract

Abstract It is now widely recognized that angiogenesis is a crucial step in the development of tumors, including hepatocellular carcinoma (HCC). Therapies targeting the tumor vessels have proven successful for cancer treatment in experimental models and, in the clinical practice, several anti-angiogenic agents have already been employed. The renin-angiotensin-aldosterone system (RAAS) has also become known as a prerequisite for tumor angiogenesis, including HCC. We previously reported that angiotensin-II (AT-II) plays an important role in HCC development, and that suppression of AT-II by angiotensin-converting enzyme (ACE) inhibitor attenuated the tumor growth of HCC via suppression of intra-tumoral angiogenesis. Recent studies have also suggested the possible involvement of aldosterone (Ald) in neovascularization, although the actual role of Ald in tumor angiogenesis is still vague. The aim of our current study was to elucidate the effect of eplerenone (Epl), a clinically used selective Ald blocker, on HCC development, especially in conjunction with angiogenesis, using subcutaneous HCC model. To create an allograft model, we injected 1×106 of BNL-HCC cells into the flanks of BALB/c mice. The administration of Epl by daily gavage at a dose of 100 mg/kg/day was started on day 14, when the mean tumor volume was ∼ 200 mm3. The tumor volume was measured twice a week, and the mice were killed 35 days after tumor cell implantation. Administration of Epl at clinically comparable low dose could suppress HCC development as compared with the non-treated control. Epl treatment resulted in a marked increase of TUNEL-positive apoptosis in the tumor, whereas Ki67-positive tumor cell proliferation was not altered. Both CD31-immunopositive neo-vessels and VEGF expression in the tumor were markedly suppressed by this treatment in a magnitude similar to the inhibitory effect on the tumor growth. Our in-vitro study showed that Epl significantly suppressed the Ald-induced endothelial proliferation and tubular formation via inhibition of phosphorylation of the extracellular signal-regulated kinase 1/2. On the other hand, neither Ald nor Epl affected the proliferation of HCC cells. In conclusion, these results indicated that aldosterone plays a pivotal role in HCC development via VEGF-mediated tumor angiogenesis, and that Epl may be a potential new strategy for HCC therapy in the future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2468.