title: Leukocyte trafficking is not affected by multikinase inhibitors sunitinib or sorafenib in mice.
abstract: Sunitinib and sorafenib are broad-spectrum tyrosine kinase inhibitors (TKI) targeting, for example, VEGF1-3, PDGFRb, RET, FLT3, CD117 (c-KIT) and CSF-1R cell membrane receptors thus suppressing tumor angiogenesis and cancer cell growth. Recently it has been suggested that the kinases targeted by Sunitinib and/or Sorafenib regulate leukocyte transmigration, which might in part be responsible for the often-observed reduction in tumor-associated myeloid derived suppressor cells and regulatory T cells. The aim of the current study is to determine whether sunitinib or sorafenib inhibit leukocyte extravasation. Sunitinib, sorafenib, or vehicle treated animals did not show any difference in leukocyte trafficking either in peritonitis or in vivo homing experiments, although sunitinib treatment effectively inhibited growth of B16 melanoma tumors in WT, SCID and SCID beige mice. Inhibition of tumor growth was associated with an increased number of infiltrating CD11b+ cells in the tumor, while the numbers of CD8, Gr-1 and F4/80 expressing cells were unchanged. In conclusion, the findings suggest that despite multiple targets with a potential role in leukocyte extravasation, neither sunitinib nor sorafenib effectively inhibits this process in vivo. Thus, the observed specific effect on CD11b cells among tumor infiltrating leukocytes is most likely an indirect effect.
authors.affiliation: Medicity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: Juha P
authors.initials: JP
authors.lastname: Laurila
authors.affiliation: IRCCS SDN, Naples, Italy.
authors.forename: Mikko O
authors.initials: MO
authors.lastname: Laukkanen
authors.affiliation: Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: Medicity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
authors.affiliation: Medicity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland. sirjal@utu.fi.
authors.forename: Sirpa
authors.initials: S
authors.lastname: Jalkanen
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D000077157:Sorafenib; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects
chemical_list: D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077210:Sunitinib
keywords: leukocyte traffic; migration; multikinase inhibitors