title: The Raf Kinase Inhibitor Sorafenib Inhibits JAK-STAT Signal Transduction in Human Immune Cells.
abstract: Sorafenib is an oral multikinase inhibitor that was originally developed as a Raf kinase inhibitor. We hypothesized that sorafenib would also have inhibitory effects on cytokine signaling pathways in immune cells. PBMCs from normal donors were treated with varying concentrations of sorafenib and stimulated with IFN-α or IL-2. Phosphorylation of STAT1 and STAT5 was measured by flow cytometry and confirmed by immunoblot analysis. Changes in IFN-α- and IL-2-stimulated gene expression were measured by quantitative PCR, and changes in cytokine production were evaluated by ELISA. Cryopreserved PBMCs were obtained from cancer patients before and after receiving 400 mg sorafenib twice daily. Patient PBMCs were thawed, stimulated with IL-2 or IFN-α, and evaluated for phosphorylation of STAT1 and STAT5. Pretreatment of PBMCs with 10 μM sorafenib decreased STAT1 and STAT5 phosphorylation after treatment with IFN-α or IL-2. This inhibitory effect was observed in PBMCs from healthy donors over a range of concentrations of sorafenib (5-20 μM), IL-2 (2-24 nM), and IFN-α (10(1)-10(6) U/ml). This effect was observed in immune cell subsets, including T cells, B cells, NK cells, regulatory T cells, and myeloid-derived suppressor cells. Pretreatment with sorafenib also inhibited PBMC expression of IFN-α- and IL-2-regulated genes and inhibited NK cell production of IFN-γ, RANTES, MIP1-α, and MIG in response to IFN-α stimulation. PBMCs from patients receiving sorafenib therapy showed decreased responsiveness to IL-2 and IFN-α treatment. Sorafenib is a Raf kinase inhibitor that could have off-target effects on cytokine-induced signal transduction in immune effector cells.
authors.affiliation: Department of Surgery, The Ohio State University, Columbus, OH 43210;
authors.forename: Sara E
authors.initials: SE
authors.lastname: Martin del Campo
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Kala M
authors.initials: KM
authors.lastname: Levine
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Mundy-Bosse
authors.affiliation: Department of Surgery, The Ohio State University, Columbus, OH 43210; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Valerie P
authors.initials: VP
authors.lastname: Grignol
authors.affiliation: Department of General Pediatrics, Nationwide Children's Hospital, Columbus, OH 43205;
authors.forename: Ene T
authors.initials: ET
authors.lastname: Fairchild
authors.affiliation: Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210;
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Campbell
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Prashant
authors.initials: P
authors.lastname: Trikha
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Mace
authors.affiliation: Cardiovascular Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: Bonnie K
authors.initials: BK
authors.lastname: Paul
authors.affiliation: Department of Neurological Surgery, The Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;
authors.forename: Alena Cristina
authors.initials: AC
authors.lastname: Jaime-Ramirez
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Joseph
authors.initials: J
authors.lastname: Markowitz
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Detroit, MI 48201;
authors.forename: Sri Vidya
authors.initials: SV
authors.lastname: Kondadasula
authors.affiliation: Kitsap General Surgery, Silverdale, WA 98383;
authors.forename: Kristan D
authors.initials: KD
authors.lastname: Guenterberg
authors.affiliation: Department of Internal Medicine, Barnes-Jewish Hospital, St. Louis, MO 63110;
authors.forename: Susan
authors.initials: S
authors.lastname: McClory
authors.affiliation: Department of Psychiatry, University of Hawaii, Honolulu, HI 96813;
authors.forename: Volodymyr I
authors.initials: VI
authors.lastname: Karpa
authors.affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210;
authors.forename: Xueliang
authors.initials: X
authors.lastname: Pan
authors.affiliation: Medical Oncology, The Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Olencki
authors.affiliation: Medical Oncology, The Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;
authors.forename: J Paul
authors.initials: JP
authors.lastname: Monk
authors.affiliation: Medical Oncology, The Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;
authors.forename: Amir
authors.initials: A
authors.lastname: Mortazavi
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Department of Pulmonary, Allergy, Critical Care and Sleep, The Ohio State University, Columbus, OH 43210;
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Medical Oncology, The Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Department of Internal Medicine, The Ohio State University, Columbus, OH 43210; and.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Department of Internal Medicine, The Ohio State University, Columbus, OH 43210; and Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Medical Oncology, The Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;
authors.forename: Manisha H
authors.initials: MH
authors.lastname: Shah
authors.affiliation: Department of Surgery, The Ohio State University, Columbus, OH 43210; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210 William.Carson@osumc.edu.
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D016898:Interferon-alpha / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000378:metabolism*; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D013964:Thyroid Neoplasms / Q000097:blood / Q000188:drug therapy; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D007376:Interleukin-2; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D009536:Niacinamide; D000077157:Sorafenib; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D048490:raf Kinases