The Raf Kinase Inhibitor Sorafenib Inhibits JAK-STAT Signal Transduction in Human Immune Cells

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 sti...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2015-09, Vol.195 (5), p.1995-2005
Main Authors: Martin del Campo, Sara E, Levine, Kala M, Mundy-Bosse, Bethany L, Grignol, Valerie P, Fairchild, Ene T, Campbell, Amanda R, Trikha, Prashant, Mace, Thomas A, Paul, Bonnie K, Jaime-Ramirez, Alena Cristina, Markowitz, Joseph, Kondadasula, Sri Vidya, Guenterberg, Kristan D, McClory, Susan, Karpa, Volodymyr I, Pan, Xueliang, Olencki, Thomas E, Monk, J Paul, Mortazavi, Amir, Tridandapani, Susheela, Lesinski, Gregory B, Byrd, John C, Caligiuri, Michael A, Shah, Manisha H, Carson, 3rd, William E
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Cells, Cultured
Dose-Response Relationship, Drug
Flow Cytometry
Gene Expression - drug effects
Humans
Immunoblotting
Interferon-alpha - pharmacology
Interleukin-2 - pharmacology
Janus Kinase 1 - metabolism
K562 Cells
Leukocytes, Mononuclear - drug effects
Leukocytes, Mononuclear - immunology
Leukocytes, Mononuclear - metabolism
Lymphocytes - drug effects
Lymphocytes - metabolism
Mice, Inbred BALB C
Niacinamide - analogs & derivatives
Niacinamide - pharmacology
Phenylurea Compounds - pharmacology
Phosphorylation - drug effects
Protein Kinase Inhibitors - pharmacology
raf Kinases - antagonists & inhibitors
raf Kinases - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction - drug effects
STAT1 Transcription Factor - metabolism
STAT5 Transcription Factor - metabolism
Thyroid Neoplasms - blood
Thyroid Neoplasms - drug therapy
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1400084