title: An oestrogen receptor β-selective agonist exerts anti-neoplastic effects in experimental intrahepatic cholangiocarcinoma.
abstract: BACKGROUND
  Cholangiocarcinoma cells over-express oestrogen receptor-β, which displays anti-proliferative and pro-apoptotic effects.
  
  
  OBJECTIVE
  To evaluate the effects of a newly developed and highly selective oestrogen receptor-β 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-β silencing (by small interfering RNA), HepG2 cells (oestrogen receptor-α and oestrogen receptor-β negative) and HepER3 cells (HepG2 cells transformed to stably express oestrogen receptor-α) 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-α and β (HepG2) and in cells expressing only oestrogen receptor-α (HepER3); its pro-apoptotic effect was impaired in cells where oestrogen receptor-β 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-β, suggesting that oestrogen receptor-β selective agonists may be a novel and effective therapeutic option for the medical treatment of intrahepatic cholangiocarcinoma.
authors.affiliation: Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.forename: Alessia
authors.initials: A
authors.lastname: Torrice
authors.forename: Stefania
authors.initials: S
authors.lastname: Saccomanno
authors.forename: Chiara
authors.initials: C
authors.lastname: Rychlicki
authors.forename: Laura
authors.initials: L
authors.lastname: Agostinelli
authors.forename: Irene
authors.initials: I
authors.lastname: Pierantonelli
authors.forename: Patrik
authors.initials: P
authors.lastname: Rhönnstad
authors.forename: Luciano
authors.initials: L
authors.lastname: Trozzi
authors.forename: Theresa
authors.initials: T
authors.lastname: Apelqvist
authors.forename: Raffaele
authors.initials: R
authors.lastname: Gentile
authors.forename: Cinzia
authors.initials: C
authors.lastname: Candelaresi
authors.forename: Giammarco
authors.initials: G
authors.lastname: Fava
authors.forename: Rossella
authors.initials: R
authors.lastname: Semeraro
authors.forename: Antonio
authors.initials: A
authors.lastname: Benedetti
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Antonio
authors.initials: A
authors.lastname: Franchitto
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.forename: Samuele
authors.initials: S
authors.lastname: De Minicis
authors.forename: Guido
authors.initials: G
authors.lastname: Carpino
authors.forename: Elisabet
authors.initials: E
authors.lastname: Kallin
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Stefan
authors.initials: S
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012334:RNA, Neoplasm; D051381:Rats; D017208:Rats, Wistar; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D047629:Estrogen Receptor beta; D012334:RNA, Neoplasm; D020845:Selective Estrogen Receptor Modulators