The selective inhibitor of nuclear export (SINE) verdinexor exhibits biologic activity against canine osteosarcoma cell lines
| Autor: | Alexander E. Davies, M.R. Watts, Justin T. Breitbach, Joelle M. Fenger, Savannah J. Tobin, Darian S. Louke |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
040301 veterinary sciences
comparative oncology Active Transport Cell Nucleus Canine Osteosarcoma doxorubicin 0403 veterinary science 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Dogs Cell Line Tumor medicine Animals Doxorubicin Viability assay Dog Diseases Caspase Acrylamides Biological Products Osteosarcoma General Veterinary biology Osteoblast 04 agricultural and veterinary sciences Original Articles In vitro medicine.anatomical_structure Hydrazines chemistry Cell culture 030220 oncology & carcinogenesis dog Cancer research biology.protein XPO1 Original Article Growth inhibition medicine.drug |
| Zdroj: | Veterinary and Comparative Oncology |
| ISSN: | 1476-5829 1476-5810 |
| Popis: | Verdinexor (KPT‐335) is a novel orally bioavailable selective inhibitor of nuclear export (SINE) compound that inhibits the function of the nuclear export protein Exportin 1 (XPO1/CRM1). In the present study, we sought to characterize the expression of XPO1 in primary canine osteosarcoma (OS) tumour samples, OS cell lines and normal osteoblasts and evaluate the in vitro activity of verdinexor alone or in combination with doxorubicin. Canine OS cell lines and a subset of primary OS tumours showed increased XPO1 transcript and protein expression as compared with normal canine osteoblast cells. All canine OS cell lines exhibited dose‐dependent growth inhibition and increased caspase 3,7 activity in response to low nanomolar concentrations of verdinexor (IC50 concentrations ranging from 21 to 74 nM). Notably, growth inhibition of normal canine osteoblast cell lines treated with verdinexor was observed at high micromolar concentrations (IC50 = 21 μM). The combination of verdinexor and doxorubicin resulted in potent inhibition of cell viability and demonstrated synergetic activity in three canine OS cell lines. Concordantly, OS cell lines showed increased γH2A.X foci following treatment with doxorubicin and recovery in verdinexor compared with cells treated with doxorubicin and recovered in normal media for 24 hours. These findings demonstrate that verdinexor has biologic activity against canine OS cell lines at physiologically relevant doses and suggest that XPO1 inhibition in combination with standard doxorubicin treatment offers promising potential for chemotherapeutic intervention in canine OS. |
| Databáze: | OpenAIRE |
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