Zhao W, Gu Y H, Song R, Qu B Q, Xu Q
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
Leukemia. 2008 Jun;22(6):1226-33. doi: 10.1038/leu.2008.58. Epub 2008 Mar 13.
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.
索拉非尼是一种用于转移性肾癌的新型药物，对多种酪氨酸激酶具有广谱活性，包括Raf-1、血管内皮生长因子受体和血小板衍生生长因子受体。然而，其对免疫系统的影响却知之甚少。在本报告中，我们研究了索拉非尼对人外周血T细胞增殖和活化的影响，以及其对小鼠T细胞介导的免疫反应的影响。在与患者使用浓度相似的情况下，索拉非尼在体外抑制原代人T细胞的增殖。在浓度超过10微摩尔时，即使停药后，索拉非尼也会导致无法恢复的增殖抑制。此外，索拉非尼在浓度高于10微摩尔时诱导T细胞凋亡。索拉非尼还导致T细胞出现G(0)/G(1)期阻滞、抑制CD25和CD69表达、抑制白细胞介素-2产生以及抑制LCK磷酸化；所有这些效应均呈现剂量和时间依赖性。在对小鼠接触性皮炎进行测试时，索拉非尼显著减轻了由苦味酸氯诱导的耳部肿胀。这些发现表明，索拉非尼可能通过诱导凋亡和靶向LCK导致T细胞免疫反应丧失。这可能会导致癌症患者出现免疫抑制。
