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

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• 作者：Marco Marzioni^a ; Alessia Torrice^b ; Stefania Saccomanno^a ; Chiara Rychlicki^a ; Laura Agostinelli^a ; Irene Pierantonelli^a ; Patrik Rhö ; nnstad^d ; Luciano Trozzi^a ; Theresa Apelqvist^d ; Raffaele Gentile^b ; Cinzia Candelaresi^a ; Giammarco Fava^a ; Rossella Semeraro^b ; Antonio Benedetti^a ; Eugenio Gaudio^c ; Antonio Franchitto^c ; Paolo Onori^c ; Samuele De Minicis^a ; Guido Carpino^c ; Elisabet Kallin^d ; Domenico Alvaro^b ; ¹ ; ^{domenico.alvaro@uniroma1.it} ; Stefan Nilsson^d ; ¹
• 关键词：Apoptosis ; Cholangiocarcinoma ; Cholangiocytes ; Oestrogen receptors ; Oestrogen receptor ¦Â agonist
• 刊名：Digestive and Liver Disease
• 出版年：2012
• 出版时间：February 2012
• 年：2012
• 卷：44
• 期：2
• 页码：134-142
• 全文大小：1518 K

文摘

Background

Cholangiocarcinoma cells over-express oestrogen receptor-¦Â, which displays anti-proliferative and pro-apoptotic effects.

Aim

To evaluate the effects of a newly developed and highly selective oestrogen receptor-¦Â 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-¦Â silencing (by small interfering RNA), HepG2 cells (oestrogen receptor-¦Á and oestrogen receptor-¦Â negative) and HepER3 cells (HepG2 cells transformed to stably express oestrogen receptor-¦Á) 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-¦Á and ¦Â (HepG2) and in cells expressing only oestrogen receptor-¦Á (HepER3); its pro-apoptotic effect was impaired in cells where oestrogen receptor-¦Â 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-¦Â, suggesting that oestrogen receptor-¦Â selective agonists may be a novel and effective therapeutic option for the medical treatment of intrahepatic cholangiocarcinoma.