A specific inhibitor of TGF-β receptor kinase, SB-431542, as a potent antitumor agent for human cancers
A specific inhibitor of TGF-β receptor kinase, SB-431542, as a potent antitumor agent for human cancers
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DOI：
10.1593/neo.04640
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发表时间：
2005-05-01
期刊：
影响因子：
4.8
通讯作者：
Datta, PK
中科院分区：
文献类型：
--
作者：
Halder, SK;Beauchamp, RD;Datta, PK
信号通路的小分子抑制剂已被证明对于人类癌症治疗策略的开发极其有用。在晚期癌发生过程中阻断转化生长因子-β (TGF-β) 的肿瘤促进作用为治疗干预提供了一个潜在有趣的药物靶点。尽管现在临床前研究中出现的 TGF-β 受体激酶抑制剂 (TRKI) 很少，但对于这些抑制剂如何调节 TGF-β 的肿瘤抑制或肿瘤促进作用，或者这些抑制剂何时可用于癌症进展期间的治疗，我们一无所知。我们研究了 TRKI 在临床前模型中新治疗方法的潜力。在这里，我们证明 TRKI，SB-431542，抑制 TGF-β 诱导的转录、基因表达、细胞凋亡和生长抑制。我们观察到，SB-431542 减弱了 TGF-β 的肿瘤促进作用，包括 TGF-β 诱导的 EMT、细胞运动、迁移和侵袭，以及人类癌细胞系中血管内皮生长因子的分泌。有趣的是，SB-431542 可诱导受 TGF-β 抑制生长的细胞的贴壁独立生长，而减少受 TGF-β 促进生长的细胞的集落形成。然而，SB-431542 对未能对 TGF-β 做出反应的细胞系没有影响。这代表了这些抑制剂作为人类癌症治疗剂的一种新的潜在应用，当肿瘤对 TGF-β 诱导的肿瘤抑制功能无效但对 TGF-β 的肿瘤促进作用有反应时，其目标是阻止肿瘤侵袭、血管生成和转移。
Small molecule inhibitors of signaling pathways have proven to be extremely useful for the development of therapeutic strategies for human cancers. Blocking the tumor-promoting effects of transforming growth factor-beta (TGF-beta) in advanced stage carcinogenesis provides a potentially interesting drug target for therapeutic intervention. Although very few TGF-beta receptor kinase inhibitors (TRKI) are now emerging in preclinical studies, nothing is known about how these inhibitors might regulate the tumor-suppressive or tumor-promoting effects of TGF-beta, or when these inhibitors might be useful for treatment during cancer progression. We have investigated the potential of TRKI in new therapeutic approaches in preclinical models. Here, we demonstrate that the TRKI, SB-431542, inhibits TGF-beta-induced transcription, gene expression, apoptosis, and growth suppression. We have observed that SB-431542 attenuates the tumor-promoting effects of TGF-beta, including TGF-beta-induced EMT, cell motility, migration and invasion, and vascular endothelial growth factor secretion in human cancer cell lines. Interestingly, SB-431542 induces anchorage independent growth of cells that are growth-inhibited by TGF-beta, whereas it reduces colony formation by cells that are growth-promoted by TGF-beta. However, SB-431542 has no effect on a cell line that failed to respond to TGF-beta. This represents a novel potential application of these inhibitors as therapeutic agents for human cancers with the goal of blocking tumor invasion, angiogenesis, and metastasis, when tumors are refractory to TGF-beta-induced tumor-suppressor functions but responsive to tumor-promoting effects of TGF-beta.