Alexandra Keller1,2, Bettina Wingelhofer3, Barbara Peter1,2, Karin Bauer1, Daniela Berger1, Susanne Gamperl1, Martin Reifinger4, Sabine Cerny-Reiterer1,2, Richard Moriggl3, Michael Willmann5, Peter Valent1,2, Emir Hadzijusufovic1,2,5. 1. Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria. 2. Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria. 3. Ludwig Boltzmann Institute for Cancer Research, Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria. 4. Institute of Pathology and Forensic Veterinary Medicine, Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria. 5. Department of Companion Animals and Horses, Small Animal Clinic, Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria.
Abstract
BACKGROUND: Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In non-resectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma. MATERIALS AND METHODS: We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1. RESULTS: Activated JAK2 and STAT5 were detected in both cell lines. The drugs applied were found to inhibit proliferation and survival in these cells with the following rank-order of potency: R763 > TG101348 > AZD1480 > pimozide > ruxolitinib > piceatannol. Moreover, synergistic anti-neoplastic effects were obtained by combining pimozide with KIT-targeting drugs (toceranib, masitinib, nilotinib, midostaurin) in NI-1 cells. CONCLUSION: The JAK2/STAT5 pathway is a novel potential target of therapy in canine mastocytoma.
BACKGROUND: Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In non-resectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma. MATERIALS AND METHODS: We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1. RESULTS: Activated JAK2 and STAT5 were detected in both cell lines. The drugs applied were found to inhibit proliferation and survival in these cells with the following rank-order of potency: R763 > TG101348 > AZD1480 > pimozide > ruxolitinib > piceatannol. Moreover, synergistic anti-neoplastic effects were obtained by combining pimozide with KIT-targeting drugs (toceranib, masitinib, nilotinib, midostaurin) in NI-1 cells. CONCLUSION: The JAK2/STAT5 pathway is a novel potential target of therapy in canine mastocytoma.
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