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: Megan N Breit, William C Kisseberth, Misty D Bear, Yosef Landesman, Trinayan Kashyap, Dilara McCauley, Michael G Kauffman, Sharon Shacham, Cheryl A London
• Journal: BMC veterinary research (BMC Vet Res) Vol. 10 Pg. 160 (Jul 15 2014) ISSN: 1746-6148 [Electronic] England
• PMID: 25022346 (Publication Type: Journal Article)

Chemical References

• Acrylamides
• Antineoplastic Agents
• Cyclin-Dependent Kinase Inhibitor p21
• Hydrazines
• Karyopherins
• Receptors, Cytoplasmic and Nuclear
• Tumor Suppressor Protein p53
• exportin 1 protein
• verdinexor

Topics

• Acrylamides (administration & dosage, pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Biological Availability
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Dogs
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Neoplastic (drug effects)
• Hydrazines (administration & dosage, pharmacology)
• Karyopherins (genetics, metabolism)
• Melanoma
• Receptors, Cytoplasmic and Nuclear (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)