title: Sorafenib inhibits activation of human peripheral blood T cells by targeting LCK phosphorylation.
abstract: Sorafenib, a novel drug for metastatic renal cancer, has broad-spectrum activity against multiple tyrosine kinases, including Raf-1, vascular endothelial growth factor receptor and platelet-derived growth factor receptor. However, little is known about its effects on the immune system. In this report, we examine the effects of sorafenib on the proliferation and activation of human peripheral blood T cells, as well as its effects on T-cell-mediated immune response in mice. At concentrations similar to those used in patients, sorafenib inhibited the proliferation of primary human T cells in vitro. At more than 10 microM, sorafenib caused an irrecoverable inhibition of proliferation, even after drug withdrawal. In addition, sorafenib induced T-cell apoptosis at concentrations higher than 10 muM. sorafenib also caused G(0)/G(1) phase arrest, inhibition of CD25 and CD69 expression, interleukin-2 production and LCK phosphorylation in the T cells; all of these effects exhibited dose and time dependence. When tested against contact dermatitis in mice, sorafenib significantly reduced the ear swelling induced by picryl chloride. These findings suggest that sorafenib may cause the loss of T-cell immune response by inducing apoptosis and targeting LCK. This could potentially lead to immunosuppression in patients with cancer.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhao
authors.forename: Y H
authors.initials: YH
authors.lastname: Gu
authors.forename: R
authors.initials: R
authors.lastname: Song
authors.forename: B Q
authors.initials: BQ
authors.lastname: Qu
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology*; D001773:Blood Cells / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D006968:Hypersensitivity, Delayed; D007114:Immunization; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D017386:Sequence Homology, Amino Acid; D000077157:Sorafenib; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D048049:Extracellular Signal-Regulated MAP Kinases; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D020930:MAP Kinase Kinase Kinases; D009536:Niacinamide; D010671:Phenylurea Compounds; D019908:Proto-Oncogene Proteins c-raf; D011725:Pyridines; D040262:Receptors, Vascular Endothelial Growth Factor; D000077157:Sorafenib; D000099192:CD69 Antigens