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EW-7195, a novel inhibitor of ALKS kinase inhibits EMT and breast cancer metastasis to lung
Yhun Yhong, Sheen,Chul-Yong, Park,Jee-Yeon, Son,Cheng Hua, Jin,Jeong-Suk, Nam,Dae-Kee, Kim 梨花女子大學校 藥學硏究所 2012 藥學硏究論文集 Vol.- No.22
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)-1H-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-β(1)-stimulated transcriptional activations of p3TP-Lux and pCAGA(12)-Luc. In addition, EW-7195 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 increased by TGF-β(1). In addition, EW-7195 inhibited TGF-β(1)-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-β(1)-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.
Cinvited Review : Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy
( Yhun Yhong Sheen ),( Min Jin Kim ),( Sang A Park ),( So Yeon Park ),( Jeong Seok Nam ) 한국응용약물학회 2013 Biomolecules & Therapeutics(구 응용약물학회지) Vol.21 No.5
TGF-β pathway is being extensively evaluated as a potential therapeutic target. The transforming growth factor-β (TGF-β) signaling pathway has the dual role in both tumor suppression and tumor promotion. To design cancer therapeutics successfully, it is important to understand TGF-β related functional contexts. This review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression and promotion by TGF-β. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. The TGF-β inhibitors in pre-clinical studies, and Phase I and II clinical trials are updated.
Anti-Cancer Effect of IN-2001 in MDA-MB-231 Human Breast Cancer
( Yhun Yhong Sheen ),( Ki Eun Joung ),( Kyung Nan Min ),( Dae-kee Kim ) 한국응용약물학회 2012 Biomolecules & Therapeutics(구 응용약물학회지) Vol.20 No.3
In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specifi c anticancer activities in preclinical studies. But their precise mechanism of action has not been elucidated. In this study, a novel synthetic inhibitor of HDAC, 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide [IN-2001] was examined for its antitumor activity and the underlying molecular mechanisms of any such activity on human breast cancer cell lines. IN-2001 effectively inhibited cellular HDAC activity (IC50 = 0.585 nM) inMDA-MB-231 human breast cancer cells. IN-2001 caused a signifi cant dose-dependent inhibition of cell proliferation in estrogen receptor (ER) negative MDA-MB-231human breast cancer cells. Cell cycle analysis revealed that the growth inhibitory effects of IN-2001 might be attributed to cell cycle arrest at G0/G1 and/or G2/Mphase and subsequent apoptosis in human breast cancer cells. These events are accompanied by modulating several cell cycle and apoptosis regulatory genes such as CDK inhibitors p21WAF1 and p27KIP1 cyclin D1, and other tumor suppressor genes such as cyclin D2. Collectively, IN-2001 inhibited cell proliferation and induced apoptosis in human breast cancer cells and these fi ndings may provide new therapeutic approaches, combination of antiestrogen together with a HDAC inhibitor, in the hormonal therapy-resistant ER-negative breast cancers. In summary, our data suggest that this histone deacetylase inhibitor, IN-2001, is a novel promising therapeutic agent with potent antitumor effects against human breast cancers.
Yhun Yhang, Sheen,Minjung, Cho,Wan-Seob, Cho,Mina, Choi,Sueng Jun, Kim,Beam Seak, Han,Sheen Hee, Kim,Hyoung Oak, Kim,Ja Young, Jeong 이화여자대학교 약학연구소 2010 藥學硏究論文集 Vol.- No.20
Many approaches for the application of nano-sized particles to the human body as nanotechnology have been recently developed. The size of nanoparticles is related to their useful character and also plays a key role in toxicity. Since this surface area can interact with biological components of cells, nanoparticles can be more reactive in than larger particles. In the present study, a fluorescence dye-labeled 50, 100 and 200 nm-sized silica particle suspension was intravenously injected into mice to identify the toxicity, tissue distribution and excretion of silica nanoparticles in vivo. Incidence and severity of inflammatory response was transiently increased with injection of 200 and 100 nm silica nanoparticles within 12h. But there was no significant response related to injection of 50 nm particles. The silica particles of 50, 100 and 200 nm were cleared via urine and bile. The 50 nm silica anoparticles cleared to urine and bile than 100 nm and particles of 200 nm existed at lower concentration than other two smaller particles in urine and feces. Silica nanoparticles were trapped by macrophages in the spleen and liver and remained there until 4 weeks after the single injection.