title: Biologic activity of the novel orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 against canine melanoma cell lines.
abstract: BACKGROUND
  Exportin 1 (XPO1, also known as CRM1), is a chaperone protein responsible for the export of over 200 target proteins out of the nucleus. The expression and activity of XPO1 is upregulated in several human cancers and its expression is also linked to the development of chemotherapy resistance. Recent studies using both human and murine cancer cell lines have demonstrated that XPO1 is a relevant target for therapeutic intervention. The present study sought to characterize the biologic activity of an orally bioavailable selective inhibitor of nuclear export (SINE), KPT-335, against canine melanoma cell lines as a prelude to future clinical trials in dogs with melanoma.
  
  
  RESULTS
  We evaluated the effects of KPT-335 on 4 canine malignant melanoma cell lines and found that KPT-335 inhibited proliferation, blocked colony formation, and induced apoptosis of treated cells at biologically relevant concentrations of drug. Additionally, KPT-335 downregulated XPO1 protein while inducing a concomitant increase in XPO1 messenger RNA. Lastly, KPT-335 treatment of cell lines upregulated the expression of both protein and mRNA for the tumor suppressor proteins p53 and p21, and promoted their nuclear localization.
  
  
  CONCLUSIONS
  KPT-335 demonstrates biologic activity against canine melanoma cell lines at physiologically relevant doses, suggesting that KPT-335 may represent a viable treatment option for dogs with malignant melanoma.
authors.forename: Megan N
authors.initials: MN
authors.lastname: Breit
authors.forename: William C
authors.initials: WC
authors.lastname: Kisseberth
authors.forename: Misty D
authors.initials: MD
authors.lastname: Bear
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.forename: Trinayan
authors.initials: T
authors.lastname: Kashyap
authors.forename: Dilara
authors.initials: D
authors.lastname: McCauley
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kauffman
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Departments of Veterinary Biosciences and Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Rd,, Columbus, OH 43210, USA. london.20@osu.edu.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: London
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology*; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D008545:Melanoma; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097606:Exportin 1 Protein; D014230:Triazoles
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006834:Hydrazines; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein; C000593855:verdinexor; D014230:Triazoles