Abstract
Abstract TGF-β has multifunctional effects on carcinogenesis. In the early stage tumor, TGF-β acts as a tumor suppressor but in later stage of tumor, TGF-β promotes tumor invasiveness and metastasis. TGF-βRI kinase has been the target of anti-metastatic drugs, so we have synthesized new ALK5 inhibitor (EW-7197) and investigated anti-metastatic effects of EW-7197. The treatment of the EW-7197 also inhibited the luciferase activity in the lung of 4T1-Luc cell-orthotopic implanted mouse compared to that of untreated animal. The levels of MMP2 and MMP9 were decreased in the lung and breast tumor of the EW-7197 treated mice. To determine the inhibitory effect of EW-7197 on TGF-β1-induced transcriptional activation, we performed luciferase reporter gene assay in breast cancer cells. EW-7197 effectively blocked TGF-β1-induced luciferase activity in the cells in a dose-dependent manner. TGFß signaling, the phosphorylation of smad2/3 was decreased by EW-7197. TGFß-stimulated mesenchymal markers of epithelial mesenchymal transition (EMT) were inhibited by ALK5 inhibitor concomitant treatment. And also, EW-7197 showed higher inhibition on cell motility and cell invasion based on wound healing assay or invasion assay. Further, we investigated combination effect of EW-7197 and paclitaxel. To investigate anti-metastatic effect we did experiment on BALB/c-nu/nu MB231-luc cells xenografted mice by treating EW-7197 and paclitaxel. Both EW-7197 alone group and EW-7197 and paclitaxel combination group showed inhibition of metastasis and the expression of lung metastatic markers were inhibited. We experiment on BALB/c-nu/nu MB231 cells xenografted mice for survival analysis. EW-7197 and paclitaxel combination therapy lengthen the life span of mice. In summary, EW-7197 could be effective therapeutic choice for breast cancer metastasis. Also EW-7197 and paclitaxel combination therapy could be more effective than paclitaxel alone therapy for anti-metastatic effect and survival. Citation Format: Sol J. Kim, Jee Y. Son, Min J. Kim, Sang A. Park, Seon J. Lee, So Y. Park, Seung W. Kim, Dae-Kee Kim, Jeong S. Nam, Yhun Y. Sheen. Combination therapy of paclitaxel and EW-7197, a novel ALK5 inhibitor prolonged the life span of breast tumor bearing mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3237. doi:10.1158/1538-7445.AM2013-3237
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