Shor Audrey C, Keschman Elizabeth A, Lee Francis Y, Muro-Cacho Carlos, Letson G Douglas, Trent Jonathan C, Pledger W Jack, Jove Richard
Gonzmart Laboratory, Sarcoma Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Cancer Res. 2007 Mar 15;67(6):2800-8. doi: 10.1158/0008-5472.CAN-06-3469.
Sarcomas are rare malignant mesenchymal tumors for which there are limited treatment options. One potential molecular target for sarcoma treatment is the Src tyrosine kinase. Dasatinib (BMS-354825), a small-molecule inhibitor of Src kinase activity, is a promising cancer therapeutic agent with p.o. bioavailability. Dasatinib exhibits antitumor effects in cultured human cell lines derived from epithelial tumors, including prostate and lung carcinomas. However, the action of dasatinib in mesenchymally derived tumors has yet to be shown. Based on our previous findings of Src activation in human sarcomas, we evaluated the effects of dasatinib in 12 cultured human sarcoma cell lines derived from bone and soft tissue sarcomas. Dasatinib inhibited Src kinase activity at nanomolar concentrations in these sarcoma cell lines. Downstream components of Src signaling, including focal adhesion kinase and Crk-associated substrate (p130(CAS)), were also inhibited at similar concentrations. This inhibition of Src signaling was accompanied by blockade of cell migration and invasion. Moreover, apoptosis was induced in the osteosarcoma and Ewing's subset of bone sarcomas at nanomolar concentrations of dasatinib. Inhibition of Src protein expression by small interfering RNA also induced apoptosis, indicating that these bone sarcoma cell lines are dependent on Src activity for survival. These results show that dasatinib inhibits migration and invasion of diverse sarcoma cell types and selectively blocks the survival of bone sarcoma cells. Therefore, dasatinib may provide therapeutic benefit by preventing the growth and metastasis of sarcomas in patients.
肉瘤是罕见的恶性间充质肿瘤，其治疗选择有限。肉瘤治疗的一个潜在分子靶点是Src酪氨酸激酶。达沙替尼（BMS-354825）是一种Src激酶活性的小分子抑制剂，是一种有口服生物利用度的有前景的癌症治疗药物。达沙替尼在源自上皮性肿瘤（包括前列腺癌和肺癌）的培养人细胞系中表现出抗肿瘤作用。然而，达沙替尼在间充质来源肿瘤中的作用尚未得到证实。基于我们之前在人类肉瘤中发现的Src激活，我们评估了达沙替尼对12种源自骨肉瘤和软组织肉瘤的培养人肉瘤细胞系的影响。达沙替尼在纳摩尔浓度下抑制这些肉瘤细胞系中的Src激酶活性。Src信号的下游成分，包括粘着斑激酶和Crk相关底物（p130(CAS)），在相似浓度下也受到抑制。这种对Src信号的抑制伴随着细胞迁移和侵袭的阻断。此外，在纳摩尔浓度的达沙替尼作用下，骨肉瘤和尤文肉瘤亚型的骨肉瘤中诱导了细胞凋亡。通过小干扰RNA抑制Src蛋白表达也诱导了细胞凋亡，表明这些骨肉瘤细胞系的存活依赖于Src活性。这些结果表明，达沙替尼抑制多种肉瘤细胞类型的迁移和侵袭，并选择性地阻断骨肉瘤细胞的存活。因此，达沙替尼可能通过防止患者肉瘤的生长和转移而提供治疗益处。
