Chen Zhengming, Lee Francis Y, Bhalla Kapil N, Wu Jie
Molecular Oncology Program, SRB-3, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, and the Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, FL 33612, USA.
Mol Pharmacol. 2006 May;69(5):1527-33. doi: 10.1124/mol.105.020172. Epub 2006 Jan 25.
Abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) are key events in the pathogenesis of restenosis that undermine the long-term benefit of widely performed balloon angioplasty and stenting procedures. Platelet-derived growth factor (PDGF) is a potent mitogen and motogen for VSMCs and is known to play a prominent role in the intimal accumulation of smooth muscle cells. In this study, we analyzed the effects of a novel protein tyrosine kinase inhibitor, BMS-354825 (dasatinib), on PDGF-stimulated VSMCs. BMS-354825 is an orally bioavailable dual Src/Bcr-Abl tyrosine kinase inhibitor currently undergoing clinical trials in cancer patients. We found that BMS-354825 inhibited PDGF-stimulated activation of PDGF receptor (PDGFR), STAT3, Akt, and Erk2 in rat A10 VSMCs and in primary cultures of human aortic smooth muscle cells (AoSMCs) at low nanomolar concentrations. The 50% inhibition of the PDGFRbeta tyrosine kinase activity in vitro by BMS-354825 was observed at 4 nM. Direct comparison of BMS-354825 and another PDGFR inhibitor, imatinib (Gleevec, STI571), in VSMCs indicated that BMS-354825 is 67-fold more potent than imatinib in inhibition of PDGFR activation. BMS-354825 also inhibited Src tyrosine kinase in A10 cells. At the cell level, PDGF stimulated migration and proliferation of A10 cells and human AoSMCs, both of which were inhibited by BMS-354825 in a concentration dependent manner in the low nanomolar range. These results suggest that BMS-354825 is a potent inhibitor of PDGF-stimulated VSMC activities and a potential agent for the development of a new therapy for vascular obstructive diseases such as restenosis.
血管平滑肌细胞（VSMC）的异常迁移和增殖是再狭窄发病机制中的关键事件，这削弱了广泛应用的球囊血管成形术和支架植入术的长期疗效。血小板衍生生长因子（PDGF）是一种强效的VSMC促有丝分裂剂和促运动剂，已知其在平滑肌细胞内膜积聚中起重要作用。在本研究中，我们分析了一种新型蛋白酪氨酸激酶抑制剂BMS-354825（达沙替尼）对PDGF刺激的VSMC的影响。BMS-354825是一种口服生物可利用的双Src/Bcr-Abl酪氨酸激酶抑制剂，目前正在癌症患者中进行临床试验。我们发现，BMS-354825在低纳摩尔浓度下可抑制大鼠A10 VSMC和人主动脉平滑肌细胞（AoSMC）原代培养物中PDGF刺激的PDGF受体（PDGFR）、STAT3、Akt和Erk2的激活。在体外，BMS-354825在4 nM时可观察到对PDGFRβ酪氨酸激酶活性50%的抑制。在VSMC中对BMS-354825和另一种PDGFR抑制剂伊马替尼（格列卫，STI571）进行直接比较表明，BMS-354825在抑制PDGFR激活方面比伊马替尼强67倍。BMS-354825还可抑制A10细胞中的Src酪氨酸激酶。在细胞水平上，PDGF刺激A10细胞和人AoSMC的迁移和增殖，而BMS-354825在低纳摩尔范围内以浓度依赖性方式抑制这两种细胞的迁移和增殖。这些结果表明，BMS-354825是PDGF刺激的VSMC活性的强效抑制剂，是开发针对再狭窄等血管阻塞性疾病新疗法的潜在药物。
