European journal of cancer (1990), 2011-11, Vol.47 (17), p.2642-2653
2011
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- Autor(en) / Beteiligte
- Titel
- EW-7195, a novel inhibitor of ALK5 kinase inhibits EMT and breast cancer metastasis to lung
- Ist Teil von
- European journal of cancer (1990), 2011-11, Vol.47 (17), p.2642-2653
- Ort / Verlag
- Kidlington: Elsevier Ltd
- Erscheinungsjahr
- 2011
- Quelle
- Access via ScienceDirect (Elsevier)
- Beschreibungen/Notizen
- Abstract Recently, researchers are actively pursuing efforts to develop potent and selective ALK5 (TβRI) kinase inhibitors for clinical development. In this study, the authors examined a novel small molecule inhibitor of ALK5, 3-((4-([1,2,4]triazolo[1,5- a ]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1 H -imidazol-2-yl)methylamino)benzonitrile (EW-7195) to determine if it has potential for cancer treatment. The inhibitory effects of EW-7195 on TGF-β-induced Smad signaling and epithelial-to-mesenchymal transition (EMT) were investigated in mammary epithelial cells using luciferase reporter assays, immunoblotting, confocal microscopy and wound healing assays. In addition, the suppressive effects of EW-7195 on mammary cancer metastasis to lung were examined using a Balb/c xenograft and MMTV/cNeu transgenic mice model system. The novel ALK5 inhibitor, EW-7195, inhibited the TGF-β1 -stimulated transcriptional activations of p3TP-Lux and pCAGA12 -Luc. In addition, EW-7195 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 increased by TGF-β1 . In addition, EW-7195 inhibited TGF-β1 -induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb/c and MMTV/cNeu mice, EW-7195 inhibited metastasis to lung from breast tumours. The novel ALK5 inhibitor, EW-7195, efficiently inhibited TGF-β1 -induced Smad signaling, EMT and breast tumour metastasis to the lung in vivo , demonstrating that EW-7195 has therapeutic potential for the breast cancer metastasis to the lung.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0959-8049eISSN: 1879-0852DOI: 10.1016/j.ejca.2011.07.007Titel-ID: cdi_proquest_miscellaneous_904008032
- Format
- –
- Schlagworte
- ALK5 inhibitor, Animals, Antineoplastic Agents - therapeutic use, Biological and medical sciences, Breast cancer, Breast Neoplasms - drug therapy, Cell Line, Tumor, Cell Movement - drug effects, Cell Transformation, Neoplastic - drug effects, Epithelial-Mesenchymal Transition - drug effects, Epithelial-to-mesenchymal transition, Female, Hematology, Oncology and Palliative Medicine, Hep G2 Cells - enzymology, Humans, Luciferases - metabolism, Lung Neoplasms - prevention & control, Lung Neoplasms - secondary, Medical sciences, Metastasis, Mice, Mice, Transgenic, Neoplasm Invasiveness, Pharmacology. Drug treatments, Phosphorylation - drug effects, Protein Kinase Inhibitors - pharmacology, Protein Kinase Inhibitors - therapeutic use, Protein-Serine-Threonine Kinases - antagonists & inhibitors, Pyridines - therapeutic use, Receptors, Transforming Growth Factor beta - antagonists & inhibitors, Smad2 Protein - metabolism, TGF-β, Triazoles - therapeutic use, Tumors