title: Synergistic antipancreatic tumor effect by simultaneously targeting hypoxic cancer cells with HSP90 inhibitor and glycolysis inhibitor.
abstract: OBJECTIVE
  We sought to examine the synergistic antipancreatic cancer effect by simultaneously targeting hypoxic cancer cells with heat-shock protein 90 (HSP90) inhibitor and blockade of energy production.
  
  
  METHODS
  The anticancer effects of an HSP90 inhibitor (geldanamycin) in pancreatic cells were investigated in hypoxia and normoxia. A hexokinase II inhibitor, 3-broma-pyruvate (3BrPA), was evaluated for selective glycolysis inhibition in hypoxia as a sensitizer of HSP90 inhibitor against pancreatic cancer. The HSP90 client protein degradation was monitored by Western blot. The synergistic antitumor effect of geldanamycin and 3BrPA was evaluated in a xenograft pancreatic cancer model and monitored by a noninvasive dynamic contrast-enhanced magnetic resonance imaging.
  
  
  RESULTS
  Hypoxia enhanced HIF-1alpha expression by 11-fold in pancreatic cancer cells, and HSP90 inhibitor exhibited a seven- to eightfold higher anticancer effect in hypoxia compared with normoxia via HSP90 client protein degradation. 3BrPA selectively inhibited glycolysis and sensitized geldanamycin against pancreatic cancer cells by 17- to 400-fold through HSP90 client protein degradation. The synergistic anticancer effect of reduced doses of geldanamycin and 3-BrPA was confirmed in xenograft models in vivo by more than 75% tumor growth inhibition.
  
  
  CONCLUSIONS
  The combination of HSP90 inhibitors and glycolysis inhibitors provides preferential inhibition of cancer cells in hypoxia through HSP90 client protein degradation and selective glycolysis inhibition. This may provide a new therapeutic regimen to battle chemotherapy-resistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity.
authors.affiliation: Drug Discovery Support, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
authors.forename: Xianhua
authors.initials: X
authors.lastname: Cao
authors.forename: Mark
authors.initials: M
authors.lastname: Bloomston
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Frankel
authors.forename: Guang
authors.initials: G
authors.lastname: Jia
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Hall
authors.forename: Regina M
authors.initials: RM
authors.lastname: Koch
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.forename: Michael V
authors.initials: MV
authors.lastname: Knopp
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016227:Benzoquinones / Q000008:administration & dosage*; D015687:Cell Hypoxia / Q000187:drug effects; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005260:Female; D006019:Glycolysis / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006593:Hexokinase / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage*; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011773:Pyruvates / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011773:Pyruvates; C017092:bromopyruvate; D006593:Hexokinase; C001277:geldanamycin