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https://www.readbyqxmd.com/read/29146887/targeted-therapy-of-gastroenteropancreatic-neuroendocrine-tumours-preclinical-strategies-and-future-targets
#1
Elke Tatjana Aristizabal Prada, Christoph J Auernhammer
Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mTOR-inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression free survival due to tumor resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP-system are needed. This paper reviews preclinical research models and signaling pathways in NETs of the GEP-system...
November 16, 2017: Endocrine Connections
https://www.readbyqxmd.com/read/29141923/src-family-kinase-inhibitors-blunt-the-pacap-induced-pac1-receptor-endocytosis-phosphorylation-of-erk-and-increase-in-cardiac-neuron-excitability
#2
John D Tompkins, Todd A Clason, Thomas R Buttolph, Beatrice M Girard, Anne K Linden, Jean C Hardwick, Laura A Merriam, Victor May, Rodney L Parsons
Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) activation of PAC1 receptors (Adcyap1r1) significantly increases excitability of guinea pig cardiac neurons. This modulation of excitability is mediated in part by plasma membrane G protein-dependent activation of adenylyl cyclase and downstream signaling cascades. However, additional mechanisms responsible for the enhanced excitability are activated following internalization of the PAC1 receptor and endosomal signaling. Src family kinases play critical roles mediating endocytosis of many trophic factor and G-protein coupled receptors...
November 15, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29140740/upregulation-of-tyrosine-kinase-fyn-in-human-thyroid-carcinoma-role-in-modulating-tumor-cell-proliferation-invasion-and-migration
#3
Jing Zheng, Huiling Li, Dongting Xu, Huijuan Zhu
Tyrosine kinase FYN-a member of the SRC family of kinases-is associated with mediating mitogenic signals and regulating cell cycle entry, growth, and proliferation. It was hypothesized that FYN is upregulated in thyroid carcinoma, which plays a critical role in tumorigenesis. FYN expression level in thyroid carcinoma tissue and tumor cell lines was determined. Also, the effects of FYN on thyroid cancer (TC) growth, signaling, cell cycle, and apoptosis were evaluated in vitro. FYN was knocked down in thyroid cancer cells (TPC-1) by siRNA to investigate the effects on cell proliferation, invasion, and migration...
November 2017: Cancer Biotherapy & Radiopharmaceuticals
https://www.readbyqxmd.com/read/29137389/targeting-src-attenuates-peritoneal-fibrosis-and-inhibits-the-epithelial-to-mesenchymal-transition
#4
Jun Wang, Li Wang, Liuqing Xu, Yingfeng Shi, Feng Liu, Hualin Qi, Na Liu, Shougang Zhuang
Src has been reported to mediate tissue fibrosis in several organs, but its role in peritoneal fibrosis remains unknown. In this study, we evaluated the therapeutic effect of KX2-391, a highly selective inhibitor of Src, on the development of peritoneal fibrosis in a rat model. Daily intraperitoneal injections of chlorhexidine gluconate induced peritoneal fibrosis, as indicated by thickening of the submesothelial area with an accumulation of collagen fibrils and activation of myofibroblasts. This was accompanied by time-dependent phosphorylation of Src at tyrosine 416...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29137326/overexpression-of-carbonic-anhydrase-ix-induces-cell-motility-by-activating-matrix-metalloproteinase-9-in-human-oral-squamous-cell-carcinoma-cells
#5
Jia-Sin Yang, Chiao-Wen Lin, Yi-Hsien Hsieh, Ming-Hsien Chien, Chun-Yi Chuang, Shun-Fa Yang
Oral cancer is a solid malignant tumor that is prone to occur following hypoxia. There are no clear studies showing a link between hypoxia and oral carcinogenesis. Carbonic anhydrase IX (CAIX), which is a hypoxia-induced transmembrane protein, is highly expressed in various types of human cancer. However, the effects of CAIX on the metastasis of human oral cancer cells and the underlying molecular mechanisms have not been clarified. In this study, we observed that CAIX overexpression increased the migratory and invasive abilities of SCC-9 and SAS cells...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29136335/sii-ang-ii-potentiates-insulin-receptor-signalling-and-glycogen-synthesis-in-hepatocytes
#6
Samra Joke Sanni, Christina Lyngsø, Steen Gammeltoft, Jakob Lerche Hansen
The angiotensin II type I receptor (AT1R) is involved in the regulation of cardiovascular function. Excessive activation of AT1R by angiotensin II (Ang II) leads to cardiovascular disease and may be involved in the development of insulin resistance and diabetes. Functionally selective Ang II analogues, such as the [Sar1, Ile4, Ile8]-angiotensin II (SII Ang II) analogue that only activates a subset of signalling networks have been demonstrated to have beneficial effects on cardiovascular function in certain settings, including lowering blood pressure and increasing cardiac performance...
November 14, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29132432/ac-93253-iodide-a-novel-src-inhibitor-suppresses-nsclc-progression-by-modulating-multiple-src-related-signaling-pathways
#7
Yi-Hua Lai, Sih-Yin Lin, Yu-Shan Wu, Huei-Wen Chen, Jeremy J W Chen
BACKGROUND: The tyrosine kinase Src is involved in the progression of many cancers. Moreover, inhibiting Src activity has been shown to obstruct several signaling pathways regulated by the EGFR. Thus, Src is a valuable target molecule in drug development. The purpose of this study was to identify compounds that directly or indirectly modulate Src to suppress lung cancer cell growth and motility and to investigate the molecular mechanisms underlying the effects of these compounds. METHODS: Human non-small cell lung cancer (NSCLC) cell lines (PC9, PC9/gef, A549, and H1975) with different EGFR statuses were tested by cytotoxicity and proliferation assays after AC-93253 iodide treatment...
November 13, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29125705/m-tuberculosis-mce3c-promotes-mycobacteria-entry-into-macrophages-through-activation-of-%C3%AE-2-integrin-mediated-signaling-pathway
#8
Yong Zhang, Jie Li, Bingxi Li, Jing Wang, Cui Hua Liu
Establishment of infection by facultative intracellular pathogen Mycobacterium tuberculosis (Mtb) requires adherence to and internalization by macrophages. However, the effector molecules exploited by Mtb for entry into macrophages remain to be fully understood. The mammalian cell entry (Mce) proteins play an essential role in facilitating the internalization of mycobacteria into mammalian cells. Here we characterized Mtb Mce3C as a new mycobacterial surface protein that could promote mycobacterial adhesion to and invasion of macrophages in an RGD motif-dependent manner...
November 10, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/29123263/nuclear-igf-1r-predicts-chemotherapy-and-targeted-therapy-resistance-in-metastatic-colorectal-cancer
#9
Jordi Codony-Servat, Miriam Cuatrecasas, Elena Asensio, Carla Montironi, Anna Martínez-Cardús, Mercedes Marín-Aguilera, Carlos Horndler, Eva Martínez-Balibrea, Michele Rubini, Pedro Jares, Oscar Reig, Iván Victoria, Lydia Gaba, Marta Martín-Richard, Vicente Alonso, Pilar Escudero, Carlos Fernández-Martos, Jaime Feliu, Jose Carlos Méndez, Miguel Méndez, Javier Gallego, Antonieta Salud, Federico Rojo, Antoni Castells, Aleix Prat, Rafael Rosell, Xabier García-Albéniz, Jordi Camps, Joan Maurel
BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients...
November 9, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29114475/drug-screening-to-target-nuclear-orphan-receptor-nr4a2-for-cancer-therapeutics
#10
Takefumi Komiya, Satomi Yamamoto, Anuradha Roy, Peter McDonald, Raymond P Perez
Background: Our previous study suggested NR4A2, a subfamily member of orphan nuclear receptors, is essential for survival of human cancer cells such as mucoepidermoid carcinoma (MEC). Methods: We conducted high throughput drug screening for NR4A2 inhibitors as a novel therapeutic modality. Positive screening was performed using a luciferase reporter vector containing NR4A2 binding sequence, and a CRE-reporter control vector was used to eliminate false positives...
October 2017: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/29113283/epigallocatechin-3-gallate-induces-apoptosis-in-acute-promyelocytic-leukemia-cells-via-a-shp-1-p38%C3%AE-mapk-bax-cascade
#11
Liugen Gan, Liang Zhong, Zhiling Shan, Chunlan Xiao, Ting Xu, Hao Song, Liu Li, Rong Yang, Beizhong Liu
Acute promyelocytic leukemia (APL) is characterized by a specific chromosomal translation, resulting in a fusion gene that affects the differentiation, proliferation and apoptosis of APL cells. Epigallocatechin-3-gallate (EGCG), a catechin, exhibits numerous biological functions, including antitumor activities. Previous studies have reported that EGCG induces apoptosis in NB4 cells. However, the molecular mechanism underlying EGCG-induced apoptosis remains unclear. The present study aimed to determine the molecular basis of EGCG-induced apoptosis in NB4 cells...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29107111/entinostat-reverses-cisplatin-resistance-in-esophageal-squamous-cell-carcinoma-via-down-regulation-of-multidrug-resistance-gene-1
#12
Xiao-Ping Huang, Xuan Li, Min-Yi Situ, Li-Yun Huang, Jun-Ye Wang, Tian-Cheng He, Qi-Hang Yan, Xiu-Ying Xie, Yu-Jing Zhang, Yuan-Hong Gao, Yu-Hong Li, Tie-Hua Rong, Jian-Hua Fu, Qing-Qing Cai, Ming-Rong Wang
Cisplatin resistance frequently occurs in esophageal squamous cell carcinoma (ESCC). The underlying mechanism for cisplatin resistance in ESCC remains largely obscure. Here we report that entinostat reversed cisplatin resistance in ESCC both in vitro and in vivo by induction of apoptosis and inhibition of cell proliferation, accompanied by a decrease of multidrug resistance gene 1 (MDR1), P-Src, Mcl-1, Cyclin D1 and an increase of cleaved PARP. MDR1 expression was associated with worsen survival of ESCC patients with cisplatin-based chemotherapy...
October 26, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29100798/benzo-c-1-2-5-thiadiazole-derivatives-a-new-class-of-potent-src-homology-2-domain-containing-protein-tyrosine-phosphatase-2-shp2-inhibitors
#13
Wen-Long Wang, Xiao-Yu Chen, Ya Gao, Li-Xin Gao, Li Sheng, Jingyu Zhu, Lei Xu, Zhen-Zhong Ding, Chao Zhang, Jing-Ya Li, Jia Li, Yu-Bo Zhou
The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase linked to various kinds of cancers. Consequently, SHP2 has emerged as a promising target for novel anti-cancer agents. Using scaffold-hopping strategy, a series of benzo[c][1,2,5]thiadiazole derivatives was designed from PTP1B inhibitors with 1H-2,3-Dihydroperimidine motif, synthesized and evaluated their biological activities against PTP1B and SHP2. Among them, the representative compound 11g displayed SHP2 inhibitory activity with IC50 of 2...
October 26, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29097424/the-free-fatty-acid-receptor-1-promotes-airway-smooth-muscle-cell-proliferation-through-mek-erk-and-pi3k-akt-signaling-pathways
#14
Atsuko Matoba, Nao Matsuyama, Sumire Shibata, Eiji Masaki, Charles W Emala, Kentaro Mizuta
Obesity is a risk factor for asthma and influences airway hyperresponsiveness, which is in part modulated by airway smooth muscle proliferative remodeling. Plasma free fatty acids (FFAs) levels are elevated in obese individuals, and long-chain FFAs act as endogenous ligands for the free fatty acid receptor 1 (FFAR1), which couples to both Gq and Gi proteins. We examined whether stimulation of FFAR1 induces airway smooth muscle cell proliferation through classical MEK/ERK and/or PI3K/Akt signaling pathways. The long-chain FFAs (oleic acid and linoleic acid) and a FFAR1 agonist (GW9508) induced human airway smooth muscle (HASM) cell proliferation, which was inhibited by the MEK inhibitor U0126 and the PI3K inhibitor LY294002...
November 2, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/29097117/dasatinib-synergizes-with-atra-to-trigger-granulocytic-differentiation-in-atra-resistant-acute-promyelocytic-leukemia-cell-lines-via-lyn-inhibition-mediated-activation-of-raf-1-mek-erk
#15
Ming Ding, Xiang-Qin Weng, Yan Sheng, Jing Wu, Cui Liang, Xun Cai
All-trans retinoic acid (ATRA) resistance has been a critical problem in acute promyelocytic leukemia (APL) relapsed patients. In this study, dasatinib synergized with ATRA to trigger differentiation in ATRA-resistant APL cell lines. The combined treatment activated RAF-1, MEK and ERK as well as enhanced ATRA-promoted up-regulation of the protein level of PU.1, C/EBPβ and C/EBPε. U0126 (MEK specific inhibitor) and sorafenib tosylate (RAF-1 specific inhibitor) suppressed the combined treatment-induced differentiation, ERK phosphorylation and the up-regulation of C/EBPs and PU...
October 30, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29091939/evaluation-of-the-efficacy-of-dasatinib-a-src-abl-inhibitor-in-colorectal-cancer-cell-lines-and-explant-mouse-model
#16
Aaron J Scott, Eun-Kee Song, Stacey Bagby, Alicia Purkey, Martin McCarter, Csaba Gajdos, Kevin S Quackenbush, Benjamin Cross, Todd M Pitts, Aik Choon Tan, S Gail Eckhardt, Hubert Fenton, John Arcaroli, Wells A Messersmith
BACKGROUND: Dysregulation of the Src pathway has been shown to be important at various stages of cancer. Dasatinib is a potent Src/Abl inhibitor and has demonstrated to have anti-proliferative and anti-invasive activity in many preclinical models. The objective of this study was to determine the anti-tumor activity of dasatinib using in vitro and in vivo preclinical colorectal (CRC) models. METHODS: CRC cell lines and patient-derived tumor explant (PDX) models were used to investigate the efficacy of dasatinib...
2017: PloS One
https://www.readbyqxmd.com/read/29091516/bosutinib-versus-imatinib-for-newly-diagnosed-chronic-myeloid-leukemia-results-from-the-randomized-bfore-trial
#17
Jorge E Cortes, Carlo Gambacorti-Passerini, Michael W Deininger, Michael J Mauro, Charles Chuah, Dong-Wook Kim, Irina Dyagil, Nataliia Glushko, Dragana Milojkovic, Philipp le Coutre, Valentin Garcia-Gutierrez, Laurence Reilly, Allison Jeynes-Ellis, Eric Leip, Nathalie Bardy-Bouxin, Andreas Hochhaus, Tim H Brümmendorf
Purpose Bosutinib is a potent dual SRC/ABL kinase inhibitor approved for adults with Philadelphia chromosome-positive chronic myeloid leukemia (CML) resistant and /or intolerant to prior therapy. We assessed the efficacy and safety of bosutinib versus imatinib for first-line treatment of chronic-phase CML. Methods In this ongoing, multinational, phase III study, 536 patients with newly diagnosed chronic-phase CML were randomly assigned 1:1 to receive 400 mg of bosutinib once daily (n = 268) or imatinib (n = 268)...
November 1, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29079540/il-18-contributes-to-bone-cancer-pain-by-regulating-glia-cells-and-neuron-interaction
#18
Su Liu, Yue-Peng Liu, You Lv, Jun-Li Yao, Dong-Mei Yue, Mao-Yin Zhang, Dun-Yi Qi, Gong-Jian Liu
BACKGROUND: Glia cells hyperactivity has been proposed to be responsible for chronic pain, however, the mechanisms remain unclear. IL-18, released from glial cells, has been reported to be involved in neuropathic pain. Here, we investigated the role of IL-18 in bone cancer pain. METHODS: Bone cancer pain was mimicked by injecting Walker-256 mammary gland carcinoma cells into the intramedullary space of the tibia in rats. Expression and location of IL-18 and IL-18 receptor were tested...
October 24, 2017: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/29079173/general-paucity-of-genomic-alteration-and-low-tumor-mutation-burden-in-refractory-and-metastatic-hepatoblastoma-comprehensive-genomic-profiling-study
#19
Hwajeong Lee, Tony El Jabbour, Sanaz Ainechi, Laurie M Gay, Julia A Elvin, Jo-Anne Vergilio, James Suh, Shakti H Ramkissoon, Siraj M Ali, Alexa Schrock, David Fabrizio, Garrett Frampton, Tipu Nazeer, Vincent A Miller, Philip J Stephens, Jeffrey S Ross
Hepatoblastoma (HBL) is hepatic malignancy of infants and young children which is often cured by combinations of surgery and chemotherapy. Management of refractory and metastatic HBL is challenging. Comprehensive genomic profiling was performed on 31 refractory and metastatic HBL using a hybrid-capture, adaptor ligation based next generation sequencing assay. Tumor mutation burden (TMB) was calculated from a minimum of 1.11Mb of sequenced DNA and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA)...
October 24, 2017: Human Pathology
https://www.readbyqxmd.com/read/29078898/murine-breast-cancer-mastectomy-model-that-predicts-patient-outcomes-for-drug-development
#20
Eriko Katsuta, Omar M Rashid, Kazuaki Takabe
BACKGROUND: Despite massive expenditures in preclinical studies, many breast cancer agents show efficacy in murine models but fail in human trials. In humans, metastatic disease determines survival, but preclinical murine models only evaluate drug efficacy against the primary tumor. We hypothesized that evaluating efficacy against metastatic breast cancer would more efficiently predict efficacy in a murine model than evaluating the primary tumor alone. This study (1) critically evaluated a murine tumor removal model with metastatic tumor burden quantification for breast cancer preclinical trials and (2) validated the model with an agent that previously passed preclinical trials but failed human trials...
November 2017: Journal of Surgical Research
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