title: Novel HSP90 inhibitor NVP-AUY922 enhances the anti-tumor effect of temsirolimus against oral squamous cell carcinoma.
abstract: OBJECTIVE
  Heat shock protein 90 (HSP90) and mammalian target of rapamycin (mTOR) are involved in the molecular pathogenesis of advanced oral squamous cell carcinoma. HSP90 inhibitors are capable of effectively interfering with multiple signaling pathways, including the mTOR signaling pathway. However, the combined effects of HSP90 and mTOR inhibitors on oral squamous cell carcinoma are still unknown. In this study, we investigated the dual treatment of the novel HSP90 inhibitor NVP-AUY922 and temsirolimus against oral squamous cell carcinoma.
  
  
  METHODS
  The effect of the combination of NVP-AUY922 and temsirolimus on oral squamous cell carcinoma in vitro and in vivo was determined by MTS assay and mouse xenograft models. The effect of the combination on angiogenesis was determined by tube formation assay and angioreactor.
  
  
  RESULTS
  The combination treatment of NVP-AUY922 and temsirolimus significantly inhibited the proliferation of SAS oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. We have clearly shown that the combination treatment of NVP-AUY922 and temsirolimus inhibited vascular formation both in vitro and in vivo. Moreover, the combination treatment of NVP-AUY922 and temsirolimus prolonged the survival rate in mice xenografted with oral squamous cell carcinoma.
  
  
  CONCLUSIONS
  Here, we showed the activity of a combination of mTOR and HSP90 inhibitors for the treatment of advanced oral squamous carcinoma.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan 700-8525.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Okui
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shimo
authors.forename: Takuya
authors.initials: T
authors.lastname: Fukazawa
authors.forename: Nur
authors.initials: N
authors.lastname: Mohammad Monsur Hassan
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Honami
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ibaragi
authors.forename: Munenori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
authors.forename: Akira
authors.initials: A
authors.lastname: Sasaki
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009062:Mouth Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D012118:Resorcinols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D020533:Angiogenesis Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D012118:Resorcinols; C401859:temsirolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus