Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on Src kinase for survival
Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on Src kinase for survival
复制标题
DOI：
10.1158/0008-5472.can-06-3469
复制
发表时间：
2007-03-15
期刊：
影响因子：
11.2
通讯作者：
Jove, Richard
中科院分区：
文献类型：
--
作者：
Shor, Audrey C.;Keschman, Elizabeth A.;Jove, Richard
肉瘤是罕见的恶性间叶肿瘤，其治疗选择有限。肉瘤治疗的一种潜在分子靶点是 Src 酪氨酸激酶。 Dasatinib (BMS-354825) 是一种 Src 激酶活性的小分子抑制剂，是一种有前途的癌症治疗剂，口服给药。生物利用度。达沙替尼在源自上皮肿瘤（包括前列腺癌和肺癌）的培养人类细胞系中表现出抗肿瘤作用。然而，达沙替尼在间充质来源的肿瘤中的作用尚未得到证实。基于我们之前对人类肉瘤中 Src 激活的发现，我们评估了达沙替尼在 12 种源自骨和软组织肉瘤的培养人类肉瘤细胞系中的作用。达沙替尼在这些肉瘤细胞系中以纳摩尔浓度抑制 Src 激酶活性。 Src 信号传导的下游成分，包括粘着斑激酶和 Crk 相关底物 (P130(CAS))，也在相似的浓度下受到抑制。 Src 信号传导的这种抑制伴随着细胞迁移和侵袭的阻断。此外，纳摩尔浓度的达沙替尼可诱导骨肉瘤和尤文氏骨肉瘤亚型细胞凋亡。小干扰RNA抑制Src蛋白表达也会诱导细胞凋亡，表明这些骨肉瘤细胞系的生存依赖于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，达沙替尼可以通过预防患者肉瘤的生长和转移来提供治疗益处。
Sarcomas are rare malignant mesenchyrnal 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.