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inhibitors of notch

Hiroki Hamamoto, Kentaro Maemura, Kentaro Matsuo, Kohei Taniguchi, Yoshihisa Tanaka, Sugiko Futaki, Atsushi Takeshita, Akira Asai, Michihiro Hayashi, Yoshinobu Hirose, Yoichi Kondo, Kazuhisa Uchiyama
Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. We previously showed that expression of Delta-like 3 (DLL3), a member of the family of Delta/Serrate/Lag2 ligands for the Notch receptor, is silenced by aberrant DNA methylation and that overexpression of DLL3 in an HCC cell line induces cellular apoptosis. However, how DLL3 expression is regulated during hepatocarcinogenesis is still unclear. Here, we show that silencing of DLL3 during hepatocarcinogenesis is closely related to viral infection, especially hepatitis B virus (HBV) infection (p = 0...
March 19, 2018: Scientific Reports
Anton G Kutikhin, Maxim Yu Sinitsky, Arseniy E Yuzhalin, Elena A Velikanova
The blood flow through vessels produces a tangential, or shear, stress sensed by their innermost layer (i.e., endothelium) and representing a major hemodynamic force. In humans, endothelial repair and blood vessel formation are mainly performed by circulating endothelial progenitor cells (EPCs) characterized by a considerable expression of vascular endothelial growth factor receptor 2 (VEGFR2), CD34, and CD133, pronounced tube formation activity in vitro, and strong reendothelialization or neovascularization capacity in vivo...
March 13, 2018: Journal of Molecular and Cellular Cardiology
Frank J Simutis, Thomas P Sanderson, Gary D Pilcher, Michael J Graziano
The toxicity of avagacestat, a sulfonamide-based gamma (γ)-secretase inhibitor that was in development as a treatment for Alzheimer's disease, was evaluated in a comprehensive nonclinical toxicology program that included 6-month and 1-year repeat-dose toxicity studies in rats and dogs, respectively. There was a spectrum of mechanism-based changes attributed to inhibition of Notch signaling that regulates the differentiation and proliferation of cells throughout development and in adult tissues. In both rats and dogs, ovarian follicular degeneration and atrophy and a low incidence of granulosa cell hyperplasia and benign granulosa-thecal cell tumors were observed...
February 24, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
Diana Bellavia, Rocco Palermo, Maria Pia Felli, Isabella Screpanti, Saula Checquolo
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the therapy of ALL has significantly improved, the heterogeneous genetic landscape of the disease often causes relapse, which is difficult to treat. Achieving a positive outcome for patients with relapsed or refractory ALL remains a challenging issue. The high prevalence of NOTCH-activating mutations in T-cell acute lymphoblastic leukemia (T-ALL) and the central role of NOTCH signaling in regulating cell survival and growth of ALL provide a rationale for the development of Notch signaling-targeted strategies in this disease...
March 12, 2018: Expert Opinion on Therapeutic Targets
Wen-Wei Luo, Xin-Wei Wang, Rui Ma, Fang-Lu Chi, Ping Chen, Ning Cong, Yu-Yan Gu, Dong-Dong Ren, Juan-Mei Yang
Notch inhibition is known to generate supernumerary hair cells (HCs) at the expense of supporting cells (SCs) in the mammalian inner ear. However, inhibition of Notch activity becomes progressively less effective at inducing SC-to-HC conversion in the postnatal cochlea and balance organs as the animal ages. It has been suggested that the SC-to-HC conversion capacity is inversely correlated with E-cadherin accumulation in postnatal mammalian utricles. However, whether E-cadherin localization is linked to the SC-to-HC conversion capacity in the mammalian inner ear is poorly understood...
2018: Frontiers in Molecular Neuroscience
Santiago Nahuel Villegas, Rita Gombos, Lucia García-López, Irene Gutiérrez-Pérez, Jesús García-Castillo, Diana Marcela Vallejo, Vanina Gabriela Da Ros, Esther Ballesta-Illán, József Mihály, Maria Dominguez
The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis...
March 6, 2018: Cell Reports
Yutaka Mizuno, Kentaro Maemura, Yoshihisa Tanaka, Azumi Hirata, Sugiko Futaki, Hiroki Hamamoto, Kohei Taniguchi, Michihiro Hayashi, Kazuhisa Uchiyama, Masa-Aki Shibata, Yoshinori Otsuki, Yoichi Kondo
Delta-like 3 (DLL3) is a member of the Delta/Serrate/Lag-2 family of ligands for the Notch receptor and plays a role in Notch signaling. We have previously revealed that the expression of DLL3 is silenced by aberrant DNA methylation and that overexpression of DLL3 in the HuH2 hepatocellular carcinoma (HCC) cell line induced apoptosis. In the present study, we first confirmed the methylation of DLL3 in HuH2 cells and analyzed the methylation status of the DLL3 promoter region by bisulfite sequencing. Furthermore, we investigated whether other epigenetic modifications, such as histone acetylation and histone methylation, affected the expression of DLL3...
March 5, 2018: Oncology Reports
Si Xiong, Ronghua Wang, Qian Chen, Jing Luo, Jinlin Wang, Zhenxiong Zhao, Yawen Li, Yun Wang, Xiju Wang, Bin Cheng
In this study, we investigated the role of cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC) progression. We showed that CAFs secrete high levels of IL-6, which promoted stem cell-like properties in HCC cells by activating Notch signaling through STAT3 Tyr705 phosphorylation. These effects were abolished by Notch1 shRNA knockdown in HCC cells or treatment with an IL-6 neutralizing antibody or the p-STAT3 (Tyr705) inhibitor cryptotanshinone. Xenografted liver tumors were larger in nude mice injected with HCC cells and CAFs than in those receiving HCC cells alone...
2018: American Journal of Cancer Research
Lichun Sun, Quanyong He, Cheguo Tsai, Jun Lei, Jing Chen, Lily Vienna Makcey, David H Coy
Small cell lung cancer (SCLC) is a malignant human cancer and patients have very limited benefit from traditional anticancer treatments, with a poor five-year survival rate being 10% less. In present study, we observed that Notch signalling activation induced SCLC cell growth suppression via overexpressing Notch active fragments (ICN1, ICN2, ICN3 and ICN4), implying its tumor suppressive role. The histone deacetylase (HDAC) inhibitors also displayed their suppressive effects. Valproic acid (VPA) as a HDAC inhibitor was found to suppress SCLC cell growth and cell cycle arrest at phase G1, and observed to decrease HDAC4 and increase acetylation of histone H4 (AcH4) while activating Notch signalling with an increase of Notch1, Notch target gene HES1 and p21...
2018: American Journal of Translational Research
Chia-Hao Chang, Yu-Ting Liu, Shih-Che Weng, I-Yi Chen, Po-Nien Tsao, Shin-Hong Shiao
The Notch signaling pathway is a highly evolutionarily-conserved cell-cell signaling pathway that regulates many events during development. It plays a pivotal role in the regulation of fundamental cellular processes, such as cell proliferation, stem cell maintenance, and differentiation during embryonic and adult development. However, functions of Notch signaling in Aedes aegypti, the major mosquito vector for dengue, are largely unknown. In this study, we identified a unique feature of A. aegypti Notch (AaNotch) in the control of the sterile-like phenotype in female mosquitoes...
March 5, 2018: PLoS Neglected Tropical Diseases
Jian Cui, Yanqing Wang, Baijun Dong, Lixia Qin, Chao Wang, Peijie Zhou, Xue Wang, Huiming Xu, Wei Xue, Yu-Xiang Fang, Wei-Qiang Gao
Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT-resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In this study, we found upregulated expression of Notch receptors is positive associated with ADT-resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3...
February 27, 2018: International Journal of Cancer. Journal International du Cancer
Lei Li, Li-Ping Chen, Qing-Huai Liu
AIM: To explore the effect of the Notch signaling pathway on retinal ganglion cells (RGCs) and optic nerve in rats with acute ocular hypertension (OH). METHODS: Totally 48 Sprague-Dawley (SD) rats were included, among which 36 rats were selected to establish acute OH models. OH rats received a single intravitreal injection of 2 µL phosphate buffered solution (PBS) and another group of OH rats received a single intravitreal injection of 10 µmol/L γ-secretase inhibitor (DAPT)...
2018: International Journal of Ophthalmology
Sakiko Mizuno, Masaki Yoda, Masayuki Shimoda, Kazuhiro Chiba, Masaya Nakamura, Keisuke Horiuchi
Muscle injury is one of the most common orthopedic and sports disorders. For severe cases, surgical repair may be indicated; however, other than immobilization and the administration of anti-inflammatory drugs there is currently no effective conservative treatment for this condition. Satellite cells (SCs) are muscle-specific stem cells and are indispensable for muscle regeneration after muscle injury. SCs are activated upon muscle injury to proliferate and differentiate into myoblasts, which subsequently fuse into myofibers and regenerate the damaged muscle...
February 21, 2018: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
Luca Tamagnone, Serena Zacchigna, Michael Rehman
Abstract Notch signaling is a highly conserved pathway in all metazoans, which is deeply involved in the regulation of cell fate and differentiation, proliferation and migration during development. Research in the last decades has shown that the various components of the Notch signaling cascade are either upregulated or activated in human cancers. Therefore, its downregulation stands as a promising and powerful strategy for cancer therapy. Here, we discuss the recent advances in the development of small molecule inhibitors, blocking antibodies and oligonucleotides that hinder Notch activity, and their outcome in clinical trials...
February 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Jin Shao, Yinghong Zhou, Jinying Lin, Trung Dung Nguyen, Rong Huang, Yuantong Gu, Thor Friis, Ross Crawford, Yin Xiao
Notch is actively involved in various life processes including osteogenesis; however, the role of Notch signalling in the terminal mineralisation of bone is largely unknown. In this study, it was noted that Hey1, a downstream target of Notch signalling was highly expressed in mature osteocytes compared to osteoblasts, indicating a potential role of Notch in osteocytes. Using a recently developed thermosensitive cell line (IDG-SW3), we demonstrated that dentin matrix acidic phosphoprotein 1 (DMP1) expression was inhibited and mineralisation process was significantly altered when Notch pathway was inactivated via administration of N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), an inhibitor of Notch...
February 17, 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Yitong Xu, Hongjiu Ren, Jun Jiang, Qiongzi Wang, Muli Wudu, Qingfu Zhang, Hongbo Su, Chenglong Wang, Lihong Jiang, Xueshan Qiu
Lung cancer remains the leading cause of cancer-related death worldwide. Previous studies have shown that the novel KIAA0247 gene potentially targeted by the tumor suppressor p53 may inhibit the development of several cancers. However, the exact function of KIAA0247 in non-small-cell lung cancer (NSCLC) is unknown. The purpose of this study was to clarify the role of KIAA0247 in NSCLC. KIAA0247 expression was evaluated in tumors and adjacent normal tissues of 197 NSCLC patients by immunohistochemistry and real-time PCR and analyzed for association with clinicopathological parameters...
February 16, 2018: Cancer Science
Hong-Mei Zhang, Pei Liu, Cheng Jiang, Xiao-Qing Jin, Rui-Ning Liu, Shun-Qing Li, Yan Zhao
Notch signaling pathway is involved in many physiological and pathological processes. The γ-secretase inhibitor DAPT inhibits Notch signaling pathway and promotes nerve regeneration after cerebral ischemia. However, neuroprotective effects of DAPT against acute craniocerebral injury remain unclear. In this study, we established rat model of acute craniocerebral injury, and found that with the increase of damage grade, the expression of Notch and downstream protein Hes1 and Hes5 expression gradually increased...
2018: PloS One
Bo-Jeng Wang, Pei-Yi Wu, Yun-Wen Chen, Yu-Tzu Chang, Noopur Bhore, Po-Fan Wu, Yung-Feng Liao
We have developed a pair of cell-based reporter gene assays to quantitatively measure γ-secretase cleavage of distinct substrates. This manuscript describes procedures that may be used to monitor γ-secretase-mediated cleavage of either APP-C99 or Notch, using a Gal4 promoter-driven firefly luciferase reporter system. These assays were established by stably co-transfecting HEK293 cells with the Gal4-driven luciferase reporter gene and either the Gal4/VP16-tagged C-terminal fragment of APP (APP-C99; CG cells), or the Gal4/VP16-tagged Notch-ΔE (NΔE; NG cells)...
January 25, 2018: Journal of Visualized Experiments: JoVE
Laura Marquez-Exposito, Elena Cantero-Navarro, Carolina Lavoz, Marta Fierro-Fernández, Jonay Poveda, Sandra Rayego-Mateos, Raúl R Rodrigues-Diez, José Luis Morgado-Pascual, Macarena Orejudo, Sergio Mezzano, Marta Ruiz-Ortega
Notch pathway regulates key processes in the kidney, involved in embryonic development and tissue damage. In many human chronic renal diseases a local activation of Notch pathway has been described, suggesting that several components of Notch pathway could be considered as biomarkers of renal damage. Experimental studies by genetic modulation of Notch components or pharmacological approaches by γ-secretase inhibitors have demonstrated the role of this pathway in renal regeneration renal, podocyte apoptosis, proliferation and fibroblasts activation, and induction of epithelial to mesenchymal transition of tubular epithelial cells...
February 10, 2018: Nefrología: Publicación Oficial de la Sociedad Española Nefrologia
Natalie Cook, Bristi Basu, Donna-Michelle Smith, Aarthi Gopinathan, Jeffry Evans, William P Steward, Daniel Palmer, David Propper, Balaji Venugopal, Mirela Hategan, D Alan Anthoney, Lisa V Hampson, Michael Nebozhyn, David Tuveson, Hayley Farmer-Hall, Helen Turner, Robert McLeod, Sarah Halford, Duncan Jodrell
BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m -2 , was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D)...
February 13, 2018: British Journal of Cancer
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