| Abstract |
Background: Exportin 1 (XPO1, also known as CRM1), is a protein responsible
for the export of over 200 target proteins out of the nucleus. 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 and
induced apoptosis of treated cells. Additionally, KPT-335 downregulated
XPO1 protein while inducing a concomitant increase in XPO1 messenger RNA.
Lastly, KPT-335 treatment of cell lines induced the expression of the
tumor suppressors p53 and p21, with enhanced nuclear localization.
Conclusion: 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.
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