title: Novel C-terminal Hsp90 inhibitor for head and neck squamous cell cancer (HNSCC) with in vivo efficacy and improved toxicity profiles compared with standard agents.
abstract: BACKGROUND
  Current therapies for HNSCC, especially platinum agents, are limited by their toxicities and drug resistance. This study evaluates a novel C-terminal Hsp90 inhibitor (CT-Hsp90-I) for efficacy and toxicity in vitro and in vivo in an orthotopic HNSCC model. Our hypothesis is that C-terminal inhibitors exhibit improved toxicity/efficacy profiles over standard therapies and may represent a novel group of anticancer agents.
  
  
  METHODS
  MDA-1986 HNSCC cells were treated with doses of 17-AAG or KU363 (a CT-Hsp90-I) and compared for antiproliferation by GLO-Titer and trypan blue exclusion and for apoptosis by PARP cleavage and caspase-3 inactivation by Western analysis. In vivo studies in Nu/Nu mice examined an orthotopic model of MDA-1986 cells followed by drug dosing intraperitoneally for a 21-day period (mg/kg/dose: cisplatin = 3.5, low-dose KU363 = 5, high-dose KU363 = 25, 17-AAG = 175). Tumor size, weight, and toxicity (body score) were measured 3×/week.
  
  
  RESULTS
  The IC(50) levels for KU363 = 1.2-2 μM in MDA-1986. KU363 induces apoptosis at 1 μM with cleavage of PARP and inactivation of caspase-3 levels after 24 h. Client proteins Akt and Raf-1 were also downregulated at 1-3 μM of drug. In vivo, 100% of controls had progressive disease, while 100% of cisplatin animals showed some response, all with significant systemic toxicity. High-dose KU363 showed 88% of animals responding and low-dose KU363 showed 75% responding. KU363 animals showed significantly less toxicity (P < 0.01) than cisplatin or 17-AAG.
  
  
  CONCLUSIONS
  This novel CT-Hsp90-I KU363 manifests potent anticancer activity against HNSCC, showing excellent in vivo efficacy and reduced toxicity compared with standard agents justifying future translational evaluation.
authors.affiliation: Department of Surgery, University of Kansas Medical Center, Kansas City, KS, USA. scohen@kumc.edu
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Cohen
authors.forename: Ridhwi
authors.initials: R
authors.lastname: Mukerji
authors.forename: Abbas K
authors.initials: AK
authors.lastname: Samadi
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhao
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cohen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity; D015536:Down-Regulation / Q000187:drug effects; D005347:Fibroblasts; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D053148:Caspase 3; D002945:Cisplatin