title: Inhibition of heat shock protein 90 with AUY922 represses tumor growth in a transgenic mouse model of islet cell neoplasms.
abstract: BACKGROUND
  This study was designed to evaluate the role of heat shock protein 90 (HSP90) in tumor progression of murine islet cell tumors. Blockade of HSP90 has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with AUY922, a newly developed HSP90 inhibitor, have not been examined.
  
  
  METHODS
  The carcinoid cell line BON-1 and the HSP90 inhibitor AUY922 were used to determine effects on signaling and growth in vitro. In vivo transgenic RIP1-Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or AUY922 (25 mg/kg/twice per week) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by immunohistochemistry. Quantitative real-time PCR was performed for HSP90 targets with RNA from islets isolated from treated and untreated RIP1-Tag2 mice.
  
  
  RESULTS
  HSP90 blockade impaired constitutive and growth factor-induced signaling in vitro. Moreover, HSP90 inhibition attenuated in vitro cell growth in a dose-dependent manner. In vivo, AUY922 significantly reduced tumor volume by 92% compared to untreated controls (p = 0.000), and median survival in the used transgenic mouse model was prolonged (110 vs. 119 days; p = 0.75). Quantitative real-time PCR for downstream target genes of HSP90 demonstrated significant downregulation in the islet cell tumors of RIP1-Tag2 mice treated with AUY922, confirming our ability to achieve effective pharmacologic levels of AUY922 within the desired tissue site in vivo.
  
  
  CONCLUSIONS
  This is the first study to show that the HSP90 antagonist AUY922 may provide a new option for therapy of islet cell neoplasms.
authors.affiliation: Department of Surgery, Philipps University Marburg, Marburg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Fendrich
authors.forename: Sven
authors.initials: S
authors.lastname: Wichmann
authors.forename: Dominik
authors.initials: D
authors.lastname: Wiese
authors.forename: Jens
authors.initials: J
authors.lastname: Waldmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Lauth
authors.forename: Peter
authors.initials: P
authors.lastname: Rexin
authors.forename: Carolin
authors.initials: C
authors.lastname: L-Lopez
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Detlef K
authors.initials: DK
authors.lastname: Bartsch
authors.forename: Sven A
authors.initials: SA
authors.lastname: Lang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D007555:Isoxazoles / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D012118:Resorcinols / Q000008:administration & dosage*
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007328:Insulin; D007555:Isoxazoles; D012333:RNA, Messenger; D012118:Resorcinols