title: IL-4 downregulates expression of the target receptor CD30 in neoplastic canine mast cells.
abstract: CD30 is a novel therapeutic target in human mast cell (MC) neoplasms. In this 'comparative oncology' study, we examined CD30 expression and regulation in neoplastic canine MC using a panel of immunomodulatory cytokines [interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-13 and stem cell factor (SCF)] and the canine mastocytoma cell lines NI-1 and C2. Of all cytokines tested IL-4 was found to downregulate expression of CD30 in NI-1 and C2 cells. We also found that the CD30-targeting antibody-conjugate brentuximab vedotin induces growth inhibition and apoptosis in both MC lines. Next, we asked whether IL-4-induced downregulation of CD30 interferes with brentuximab vedotin-effects. Indeed, pre-incubation of NI-1 cells with IL-4 decreased responsiveness towards brentuximab vedotin. To overcome IL-4-mediated resistance, we applied drug combinations and found that brentuximab vedotin synergizes with the Kit-targeting drugs masitinib and PKC412 in inhibiting growth of NI-1 and C2 cells. In summary, CD30 is a new marker and IL-4-regulated target in neoplastic canine MC.
authors: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors: K
authors: K
authors: Bauer
authors: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.|Department/Clinic for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria.
authors: E
authors: E
authors: Hadzijusufovic
authors: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors: S
authors: S
authors: Cerny-Reiterer
authors: Department for Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors: G
authors: G
authors: Hoermann
authors: Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors: M
authors: M
authors: Reifinger
authors: Department/Clinic for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Surgery, University of Veterinary Medicine Vienna, Vienna, Austria.
authors: A
authors: A
authors: Pirker
authors: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors: P
authors: P
authors: Valent
authors: Department/Clinic for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria.
authors: M
authors: http://orcid.org/0000-0002-4260-1491
authors: M
authors: Willmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D000079963:Brentuximab Vedotin; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004283:Dog Diseases / Q000378:metabolism*; D004285:Dogs; D015536:Down-Regulation; D004357:Drug Synergism; D005260:Female; D018796:Immunoconjugates / Q000494:pharmacology; D015847:Interleukin-4 / Q000502:physiology*; D017730:Ki-1 Antigen / Q000378:metabolism*; D008297:Male; D008415:Mastocytosis / Q000378:metabolism / Q000662:veterinary*; D010880:Piperidines; D011725:Pyridines; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016207:Cytokines; D018796:Immunoconjugates; D017730:Ki-1 Antigen; D010880:Piperidines; D011725:Pyridines; D013844:Thiazoles; D015847:Interleukin-4; D000079963:Brentuximab Vedotin; D019311:Staurosporine; C059539:midostaurin; C526575:masitinib
keywords: CD30; IL-4; PKC412; brentuximab vedotin; canine mastocytoma; masitinib