title: Human Genetic Relevance and Potent Antitumor Activity of Heat Shock Protein 90 Inhibition in Canine Lung Adenocarcinoma Cell Lines.
abstract: BACKGROUND
  It has been an open question how similar human and canine lung cancers are. This has major implications in availability of human treatments for dogs and in establishing translational models to test new therapies in pet dogs. The prognosis for canine advanced lung cancer is poor and new treatments are needed. Heat shock protein 90 (HSP90) is an ATPase-dependent molecular chaperone ubiquitously expressed in eukaryotic cells. HSP90 is essential for posttranslational conformational maturation and stability of client proteins including protein kinases and transcription factors, many of which are important for the proliferation and survival of cancer cells. We investigated the activity of STA-1474, a HSP90 inhibitor, in two canine lung cancer cell lines, BACA and CLAC.
  
  
  RESULTS
  Comparative genomic hybridization analysis of both cell lines revealed genetic relevance to human non-small cell lung cancer. STA-1474 inhibited growth and induced apoptosis of both cell lines in a dose- and time-dependent manner. The ICs50 after 72 h treatment with STA-1474 were 0.08 and 0.11 μM for BACA and CLAC, respectively. When grown as spheroids, the IC50 of STA-1474 for BACA cells was approximately two-fold higher than when grown as a monolayer (0.348 μM vs. 0.168 μM), whereas CLAC spheroids were relatively drug resistant. Treatment of tumor-stromal fibroblasts with STA-1474 resulted in a dose-dependent decrease in their relative cell viability with a low IC50 of 0.28 μM.
  
  
  CONCLUSIONS
  Here we first established that lung adenocarcinoma in people and dogs are genetically and biochemically similar. STA1474 demonstrated biological activity in both canine lung cancer cell lines and tumor-stromal fibroblasts. As significant decreases in relative cell viability can be achieved with nanomolar concentrations of STA-1474, investigation into the clinical efficacy of this drug in canine lung cancer patients is warranted.
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Francisco
authors.initials: F
authors.lastname: Clemente-Vicario
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Alvarez
authors.affiliation: College of Nursing, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Jennie L
authors.initials: JL
authors.lastname: Rowell
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Satavisha
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: London
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Kisseberth
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Gwendolen
authors.initials: G
authors.lastname: Lorch
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D055028:Comparative Genomic Hybridization; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D007211:Indoles; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D014230:Triazoles; C545221:STA-1474