Abstract
Radio-resistance resulting from radiotherapy-induced fibrosis is a major clinical obstacle in breast cancer treatment because it typically leads to cancer recurrence, treatment failure, and ...patient death. Transforming growth factor-β (TGF-β) is a key signal messenger in fibrosis, which plays an important role in radiation-induced fibrosis and cancer stem cell (CSC) development, may be mediated through the generation of oxidative stress. This study was conducted to confirm the efficacy of vactosertib, a TGF-β/ALK5 inhibitor, as a potent inhibitor in radiation-induced oxidative stress generation, fibrosis and CSC development. We used a 4T1-Luc allograft BALB/c syngeneic mouse model and 4T1-Luc and MDA-MB-231 cells for histological analysis, qRT-PCR, western blotting, ROS analysis, mammosphere formation analysis, monolayer fluorescence imaging analysis. Radiotherapy induces TGF-β signaling, oxidative stress markers (4-HNE, NOX2, NOX4, PRDX1, NRF2, HO-1, NQO-1), fibrosis markers (PAI-1, α-SMA, FIBRONECTIN, COL1A1), and CSC properties. However, combination therapy with vactosertib not only inhibits these radiation-induced markers and properties by blocking TGF-β signaling, but also enhances the anticancer effect of radiation by reducing the volume of breast cancer. Therefore, these data suggest that vactosertib can effectively reduce radiation fibrosis and resistance in breast cancer treatment by inhibiting radiation-induced TGF-β signaling and oxidative stress, fibrosis, and CSC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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 12
h. 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 nanoparticles 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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Advanced tumors produce an excessive amount of transforming growth factor β (TGFβ), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGFβ ...therapeutics for cancer. We synthesized a novel small-molecule TGFβ receptor I kinase (activin receptor-like kinase 5) inhibitor termed N-4-(1,2,4triazolo1,5-apyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-ylmethyl-2-fluoroaniline (EW-7197), and we investigated its potential antimetastatic efficacy in mouse mammary tumor virus (MMTV)/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 inhibited Smad/TGFβ signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 also inhibited the epithelial-to-mesenchymal transition (EMT) in both TGFβ-treated breast cancer cells and 4T1 orthotopic-grafted mice. Furthermore, EW-7197 enhanced cytotoxic T lymphocyte activity in 4T1 orthotopic-grafted mice and increased the survival time of 4T1-Luc and 4T1 breast tumor-bearing mice. In summary, EW-7197 showed potent in vivo antimetastatic activity, indicating its potential for use as an anticancer therapy.
Background/Aims: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1α activates hepatic stellate cells (HSCs) and increases transforming growth factor-β (TGF-β) signaling and the ...epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-β type I receptor kinase, EW-7197, on HIF1α-derived TGF-β signaling in cholestatic liver fibrosis. Methods: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1α-derived TGF-β signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. Results: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1α-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1α-derived HSC activation and expression of EMT markers in LX-2 cells in vitro. Conclusion: This study suggests that EW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1α-induced TGF-β signaling.
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.
Recently, small molecule inhibitors of transforming growth factor‐β (TGF‐β) type I receptor kinase/activin receptor‐like kinase‐5 (ALK5) have been developed to target TGF‐β signalling as a ...therapeutic strategy for combating cancer. In the present study, the authors examined a novel small molecule inhibitor of ALK5, 3‐((5‐(1,2,4triazolo1,5‐apyridin‐6‐yl)‐4‐(6‐methylpyridin‐2‐yl)thiazol‐2‐ylamino)methyl)benzonitrile (EW‐7203) in breast cancer cells to determine if it has potential for cancer treatment. The inhibitory effects of EW‐7203 on TGF‐β‐induced Smad signalling 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‐7203 on mammary cancer metastasis to the lung were examined using a Balb/c xenograft model system. The novel ALK5 inhibitor, EW‐7203, inhibited the TGF‐β1‐stimulated transcriptional activation of p3TP‐Lux and pCAGA12‐Luc. In addition, EW‐7203 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 was increased by TGF‐β1. In addition, EW‐7203 inhibited TGF‐β1‐induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb/c mice, EW‐7203 inhibited metastasis to the lung from breast tumors. The novel ALK5 inhibitor, EW‐7203, efficiently inhibited TGF‐β1‐induced Smad signalling, EMT and breast tumor metastasis to the lung in vivo, demonstrating that EW‐7203 has therapeutic potential for breast cancer metastasis to the lung. (Cancer Sci 2011; 102: 1889–1896)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Transforming growth factor-β (TGF-β) signaling plays a key role in progression and metastasis of HCC. This study was undertaken to gain the proof of concept of a small-molecule inhibitor of TGF-β ...type I receptor kinase, EW-7197 as a potent anti-cancer therapy for HCC. We identified tissue inhibitors of metalloproteinases-1 (TIMP-1) as one of the secreted proteins of hepatic stellate cells (HSCs) and a key mediator of TGF-β-mediated crosstalk between HSCs and HCC cells. TGF-β signaling led to increased expression of TIMP-1, which activates focal adhesion kinase (FAK) signaling via its interaction with CD63. Inhibition of TGF-β signaling using EW-7197 significantly attenuated the progression and intrahepatic metastasis of HCC in an SK-HEP1-Luc orthotopic-xenograft mouse model. In addition, EW-7197 inhibited TGF-β-stimulated TIMP-1 secretion by HSCs as well as the TIMP-1-induced proliferation, motility, and survival of HCC cells. Further, EW-7197 interrupted TGF-β-mediated epithelial-to-mesenchymal transition and Akt signaling, leading to significant reductions in the motility and anchorage-independent growth of HCC cells. In conclusion, we found that TIMP-1 mediates TGF-β-regulated crosstalk between HSCs and HCC cells via FAK signaling. In addition, EW-7197 demonstrates potent in vivo anti-cancer therapeutic activity and may be a potential new anti-cancer drug of choice to treat patients with liver cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Recent strategies for treating CML patients have focused on investigating new combinations of tyrosine kinase inhibitors (TKIs) as well as identifying novel translational research agents that can ...eradicate CML leukemia‐initiating cells (CML‐LICs). However, little is known about the therapeutic benefits such CML‐LIC targeting therapies might bring to CML patients. In this study, we investigated the therapeutic potential of EW‐7197, an orally bioavailable transforming growth factor‐β signaling inhibitor which has recently been approved as an Investigational New Drug (NIH, USA), to suppress CML‐LICs in vivo. Compared to TKI treatment alone, administration of TKI plus EW‐7197 to CML‐affected mice significantly delayed disease relapse and prolonged survival. Notably, combined treatment with EW‐7197 plus TKI was effective in eliminating CML‐LICs even if they expressed the TKI‐resistant T315I mutant BCR‐ABL1 oncogene. Collectively, these results indicate that EW‐7197 may be a promising candidate for a new therapeutic that can greatly benefit CML patients by working in combination with TKIs to eradicate CML‐LICs.
We investigated the therapeutic potential of EW‐7197, an orally bioavailable TGF‐β signaling inhibitor, to eradicate murine CML leukemia‐initiating cells (CML‐LICs) in vivo. The combined administration of EW‐7197 plus TKI was effective in eliminating CML‐LICs even if they expressed the TKI‐resistant T315I mutant BCR‐ABL1 oncogene, indicating that EW‐7197 may be a promising candidate for a new therapeutic that can greatly benefit CML patients by working in combination with TKIs to eradicate CML‐LICs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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-(1,2,4triazolo1,5- 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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A series of 1-substituted-3-(6-methylpyridin-2-yl)-4-(1,2,4triazolo1,5-
apyridin-6-yl)pyrazoles
14a–
ae,
16a,
16b, and
21a–
c has been prepared and evaluated for their ALK5 inhibitory activity in an ...enzyme assay and in a cell-based luciferase reporter assay. The 4-(1,2,4triazolo1,5-
apyridin-6-yl)-
N-(4-methoxyphenyl)-3-(6-methylpyridin-2-yl)-1
H-pyrazole-1-carbothioamide (
14n) inhibited ALK5 phosphorylation with IC
50 value of 0.57
nM and showed 94% inhibition at 100
nM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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