Selective aldosterone blocker, eplerenone, attenuates hepatocellular carcinoma growth and angiogenesis in mice.
OBJECTIVE
The renin-angiotensin-aldosterone system (RAAS) has become known as a prerequisite for tumor angiogenesis, including hepatocellular carcinoma (HCC). Although angiotensin II is known to play an important role in tumor growth and angiogenesis, the role of aldosterone (Ald) is still obscure. The aim of our current study was to elucidate the effect of eplerenone, a clinically used selective Ald blocker (SAB), on murine HCC development especially in conjunction with angiogenesis.


METHODS
To create an allograft model, we injected 1 x 10(6) of BNL-HCC cells into the flanks of BALB/c mice. After the tumor was established, SAB was administrated at dose of 100 mg/kg per day.


RESULTS
Administration of SAB significantly suppressed HCC development along with inhibition of angiogenesis and expression of the vascular endothelial growth factor (VEGF), a potent angiogenic factor. SAB treatment resulted in a marked increase of apoptosis in the tumor, whereas tumor cell proliferation was not altered. Our in vitro study showed that SAB significantly suppressed the Ald-induced endothelial proliferation and tubular formation through inhibition of phosphorylation of the extracellular signal-regulated kinase 1/2. On the contrary, neither Ald nor SAB affected the proliferation of HCC cells in vitro.


CONCLUSIONS
Ald plays a pivotal role in HCC development through VEGF-mediated tumor angiogenesis, and SAB may be a potential new strategy in HCC therapy in the future.
Kaji
Kosuke
K
Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Yoshiji
Hitoshi
H
Kitade
Mitsuteru
M
Ikenaka
Yasuhide
Y
Noguchi
Ryuichi
R
Shirai
Yusaku
Y
Yoshii
Junichi
J
Yanase
Koji
K
Namisaki
Tadashi
T
Yamazaki
Masaharu
M
Tsujimoto
Tatsuhiro
T
Kawaratani
Hideto
H
Fukui
Hiroshi
H