An oestrogen receptor β-selective agonist exerts anti-neoplastic effects in experimental intrahepatic cholangiocarcinoma

Background: Cholangiocarcinoma cells over-express oestrogen receptor-beta, which displays anti-proliferative and pro-apoptotic effects. Aim: To evaluate the effects of a newly developed and highly selective oestrogen receptor-beta agonist (KB9520) on experimental intrahepatic cholangiocarcinoma. Methods: In vitro, the effects of KB9520 on apoptosis and proliferation of HuH-28 cells, HuH-28 cells with selective oestrogen receptor-beta silencing (by small interfering RNA), HepG2 cells (oestrogen receptor-alpha and oestrogen receptor-beta negative) and HepER3 cells (HepG2 cells transformed to stably express oestrogen receptor-alpha) were evaluated. In vivo, the effects of KB9520 on experimental intrahepatic cholangiocarcinoma, induced by thioacetamide administration were tested. Results: In vitro, KB9520 induced apoptosis and inhibited proliferation of HuH-28 cells. KB9520 effects were absent in cells lacking oestrogen receptor-alpha and beta (HepG2) and in cells expressing only oestrogen receptor-alpha (HepER3); its pro-apoptotic effect was impaired in cells where oestrogen receptor-beta expression was decreased by specific small interfering RNA. In vivo, KB9520 inhibited experimental intrahepatic cholangiocarcinoma development in thioacetamide-treated rats and promoted tumour regression in rats where tumour was already established. In treated animals, tumour areas showed reduced proliferation but increased apoptosis. Conclusions: KB9520 induced apoptosis in cholangiocarcinoma by selectively acting on oestrogen receptor-beta, suggesting that oestrogen receptor-beta selective agonists may be a novel and effective therapeutic option for the medical treatment of intrahepatic cholangiocarcinoma. (C) 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved