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https://www.readbyqxmd.com/read/27911119/phase-ii-study-of-dasatinib-in-previously-treated-patients-with-advanced-non-small-cell-lung-cancer
#1
Michael J Kelley, Gautam Jha, Debra Shoemaker, James E Herndon, Lin Gu, William T Barry, Jeffrey Crawford, Neal Ready
The Src pathway in activated in about one-third of non-small cell lung cancer (NSCLC) tumors. Dasatinib has Src-inhibitor activity. We examined the activity of dasatinib in 37 patients with advanced, previously treated NSCLC. Among the 29 patients who underwent pre-treatment biopsy for RNA biomarker analysis, 25 were treated with dasatinib 70 mg twice daily. There were no responses. Five patients discontinued treatment due to toxicity. Three patients had minor biopsy-related pneumothoraces. Given the lack of responses, no biomarkers were analyzed...
December 2, 2016: Cancer Investigation
https://www.readbyqxmd.com/read/27910855/l-type-calcium-channels-regulate-filopodia-stability-and-cancer-cell-invasion-downstream-of-integrin-signalling
#2
Guillaume Jacquemet, Habib Baghirov, Maria Georgiadou, Harri Sihto, Emilia Peuhu, Pierre Cettour-Janet, Tao He, Merja Perälä, Pauliina Kronqvist, Heikki Joensuu, Johanna Ivaska
Mounting in vitro, in vivo and clinical evidence suggest an important role for filopodia in driving cancer cell invasion. Using a high-throughput microscopic-based drug screen, we identify FDA-approved calcium channel blockers (CCBs) as potent inhibitors of filopodia formation in cancer cells. Unexpectedly, we discover that L-type calcium channels are functional and frequently expressed in cancer cells suggesting a previously unappreciated role for these channels during tumorigenesis. We further demonstrate that, at filopodia, L-type calcium channels are activated by integrin inside-out signalling, integrin activation and Src...
December 2, 2016: Nature Communications
https://www.readbyqxmd.com/read/27903968/novel-src-abl-tyrosine-kinase-inhibitor-bosutinib-suppresses-neuroblastoma-growth-via-inhibiting-src-abl-signaling
#3
Shayahati Bieerkehazhi, Zhenghu Chen, Yanling Zhao, Yang Yu, Huiyuan Zhang, Sanjeev A Vasudevan, Sarah E Woodfield, Ling Tao, Joanna S Yi, Jodi A Muscal, Jonathan C Pang, Shan Guan, Hong Zhang, Jed G Nuchtern, Hui Li, Huiwu Li, Jianhua Yang
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Aberrant activation of the non-receptor tyrosine kinases Src and c-Abl contributes to the progression of NB. Thus, targeting these kinases could be a promising strategy for NB therapy. In this paper, we report that the potent dual Src/Abl inhibitor bosutinib exerts anti-tumor effects on NB. Bosutinib inhibited NB cell proliferation in a dose-dependent manner and suppressed colony formation ability of NB cells. Mechanistically, bosutinib effectively decreased the activity of Src/Abl and PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27900636/cardamonin-represses-proliferation-invasion-and-causes-apoptosis-through-the-modulation-of-signal-transducer-and-activator-of-transcription-3-pathway-in-prostate-cancer
#4
Jingwen Zhang, Sakshi Sikka, Kodappully S Siveen, Jong Hyun Lee, Jae-Young Um, Alan Prem Kumar, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Basappa, Kanchugarakoppal S Rangappa, Gautam Sethi, Kwang Seok Ahn
The pleiotropic transcription factor, signal transducer and activator of transcription 3 (STAT3) is often aberrantly activated in a wide variety of cancers and plays a pivotal role in tumor initiation, promotion and progression. Targeting deregulated STAT3 activation by small molecule inhibitors is generally considered as an important therapeutic strategy. Hence, in the present study, we evaluated the potential of cardamonin (CD), a 2',4'-dihydroxy-6'-methoxychalcone, to modulate STAT3 activation in prostate cancer (PC) cells and found that this chalcone can indeed exhibit significant anticancer effects through negatively regulating STAT3 activation by diverse molecular mechanism(s)...
November 29, 2016: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/27900042/antitumor-activity-of-7rh-a-discoidin-domain-receptor-1-inhibitor-alone-or-in-combination-with-dasatinib-exhibits-antitumor-effects-in-nasopharyngeal-carcinoma-cells
#5
Qiu-Ping Lu, Wen-Dan Chen, Jie-Ren Peng, Yao-Dong Xu, Qian Cai, Gong-Kan Feng, Ke Ding, Xiao-Feng Zhu, Zhong Guan
Dysregulation of the discoidin domain receptors (DDRs) has been implicated in the development of numerous types of tumors, including head and neck cancer, and nasopharyngeal, breast, ovarian and esophageal carcinomas. Furthermore, agents that inhibit DDR1 activity are hypothesized to be useful for the treatment of nasopharyngeal carcinoma (NPC). The aim of the present study was to evaluate the effect of the DDR1 inhibitory (3-(2-(pyrazolo(1,5-a)pyrimidin-6-yl)-ethynyl)benzamide compound, 7RH, in NPC cells both in vitro and in vivo, and its effect when used in combination with dasatinib, a SRC family kinase (SFK) inhibitor...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27895735/crk-like-adapter-protein-is-overexpressed-in-cervical-carcinoma-facilitates-proliferation-invasion-and-chemoresistance-and-regulates-src-and-akt-signaling
#6
Hong Ji, Bo Li, Shitai Zhang, Zheng He, Yang Zhou, Ling Ouyang
Overexpression of Crk-like (CrkL) adapter protein has been implicated in a number of types of human cancer. However, its involvement in human cervical carcinoma remains unclear. The present study aimed to explore the clinical significance and biological characteristics of CrkL in human cervical carcinoma. CrkL protein expression was examined in tissue samples from 92 cases of cervical carcinoma using immunohistochemistry, and was found to be overexpressed in 48.9% (45/92 cases). CrkL was transfected into HeLa and CaSki cervical carcinoma cell lines and its effects on biological behavior were examined...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27893804/tgfbeta-induces-binucleation-polyploidization-in-hepatocytes-through-a-src-dependent-cytokinesis-failure
#7
Marco De Santis Puzzonia, Angela Maria Cozzolino, Germana Grassi, Francesca Bisceglia, Raffaele Strippoli, Giulia Guarguaglini, Franca Citarella, Benedetto Sacchetti, Marco Tripodi, Alessandra Marchetti, Laura Amicone
In all mammals, the adult liver shows binucleated as well as mononucleated polyploid hepatocytes. The hepatic polyploidization starts after birth with an extensive hepatocyte binucleation and generates hepatocytes of several ploidy classes. While the functional significance of hepatocyte polyploidy is becoming clearer, how it is triggered and maintained needs to be clarified. Aim of this study was to identify a major inducer of hepatocyte binucleation/polyploidization and the cellular and molecular mechanisms involved...
2016: PloS One
https://www.readbyqxmd.com/read/27890480/chemerin-induced-arterial-contraction-is-gi-and-calcium-dependent
#8
David J Ferland, Emma S Darios, Richard R Neubig, Benita Sjögren, Nguyen Truong, Rosa Torres, Thomas S Dexheimer, Janice M Thompson, Stephanie W Watts
Chemerin is an adipokine associated with increased blood pressure, and may link obesity with hypertension. We tested the hypothesis that chemerin-induced contraction of the vasculature occurs via calcium flux in smooth muscle cells. Isometric contraction of rat aortic rings was performed in parallel with calcium kinetics of rat aortic smooth muscle cells to assess the possible signaling pathway. Chemerin-9 (nonapeptide of the chemerin S(157) isoform) caused a concentration-dependent contraction of isolated aorta (EC50 100nM) and elicited a concentration-dependent intracellular calcium response (EC50 10nM)...
November 24, 2016: Vascular Pharmacology
https://www.readbyqxmd.com/read/27888615/unconjugated-secondary-bile-acids-activate-the-unfolded-protein-response-and-induce-golgi-fragmentation-via-a-src-kinase-dependant-mechanism
#9
Ruchika Sharma, Francis Quilty, John F Gilmer, Aideen Long, Anne-Marie Byrne
Bile acids are components of gastro-duodenal refluxate and regarded as causative agents in oesophageal disease but the precise mechanisms are unknown. Here we demonstrate that a specific subset of physiological bile acids affect the protein secretory pathway by inducing ER stress, activating the Unfolded Protein Response (UPR) and causing disassembly of the Golgi apparatus in oesophageal cells. Deoxycholic acid (DCA), Chemodeoxycholic acid (CDCA) and Lithocholic acid (LCA) activated the PERK arm of the UPR, via phosphorylation of eIF2α and up-regulation of ATF3, CHOP and BiP/GRP78...
November 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27888136/different-epigenetic-mechanisms-of-er%C3%AE-implicated-in-the-fate-of-fulvestrant-resistant-breast-cancer
#10
Kouki Tsuboi, Yosuke Kaneko, Takamasa Nagatomo, Rika Fujii, Toru Hanamura, Tatsuyuki Gohno, Yuri Yamaguchi, Toshifumi Niwa, Shin-Ichi Hayashi
Approximately 70% of breast cancers express estrogen receptor α (ERα), which plays critical roles in breast cancer development. Fulvestrant has been effectively used to treat ERα-positive breast cancer, although resistance remains a critical problem. To elucidate the mechanism of resistance to fulvestrant, we established fulvestrant-resistant cell-lines named MFR (MCF-7 derived fulvestrant resistance) and TFR (T-47D derived fulvestrant resistance) from the ERα-positive luminal breast cancer cell lines MCF-7 and T-47D, respectively...
November 22, 2016: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27881786/neuronal-dysfunction-in-ipsc-derived-medium-spiny-neurons-from-chorea-acanthocytosis-patients-is-reversed-by-src-kinase-inhibition-and-f-actin-stabilization
#11
Nancy Stanslowsky, Peter Reinhardt, Hannes Glass, Norman Kalmbach, Maximilian Naujock, Niko Hensel, Verena Lübben, Arun Pal, Anna Venneri, Francesca Lupo, Lucia De Franceschi, Peter Claus, Jared Sterneckert, Alexander Storch, Andreas Hermann, Florian Wegner
: Chorea-acanthocytosis (ChAc) is a fatal neurological disorder characterized by red blood cell acanthocytes and striatal neurodegeneration. Recently, severe cell membrane disturbances based on depolymerized cortical actin and an elevated Lyn kinase activity in erythrocytes from ChAc patients were identified. How this contributes to the mechanism of neurodegeneration is still unknown. To gain insight into the pathophysiology, we established a ChAc patient-derived induced pluripotent stem cell model and an efficient differentiation protocol providing a large population of human striatal medium spiny neurons (MSNs), the main target of neurodegeneration in ChAc...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27881656/infectious-bursal-disease-virus-activates-c-src-to-promote-%C3%AE-4%C3%AE-1-integrin-dependent-viral-entry-via-modulating-downstream-akt-rhoa-gtpase-actin-rearrangement-cascade
#12
Chengjin Ye, Xinpeng Han, Zhaoli Yu, Enli Zhang, Lijuan Wang, Hebin Liu
: While the entry of IBDV is initiated by the binding of the virus to the two major receptors integrin and HSP90, the signaling events after the receptor binding and how they contribute to the viral entry remain elusive. We show here that IBDV activates c-Src by inducing phosphorylation of the Y416 residue in c-Src both in the DF-1 chicken fibroblasts and in vivo in the bursa of fabricius from SPF chickens. Importantly, the inactivated IBDV fails to stimulate c-Src Y416 phosphorylation, and a very virulent IBDV strain induces much higher level of c-Src Y416 phosphorylation than an attenuated strain...
November 23, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27879050/structural-studies-of-protein-arginine-methyltransferase-2-reveal-its-interactions-with-potential-substrates-and-inhibitors
#13
Vincent Cura, Nils Marechal, Nathalie Troffer-Charlier, Jean-Marc Strub, Matthijs J van Haren, Nathaniel I Martin, Sarah Cianférani, Luc Bonnefond, Jean Cavarelli
: PRMT2 is the less-characterized member of the protein arginine methyltransferase family in terms of structure, activity, and cellular functions. PRMT2 is a modular protein containing a catalytic Ado-Met-binding domain and unique Src homology 3 domain that binds proteins with proline-rich motifs. PRMT2 is involved in a variety of cellular processes and has diverse roles in transcriptional regulation through different mechanisms depending on its binding partners. PRMT2 has been demonstrated to have weak methyltransferase activity on a histone H4 substrate, but its optimal substrates have not yet been identified...
November 5, 2016: FEBS Journal
https://www.readbyqxmd.com/read/27875952/in-vitro-sensitivity-profiling-of-neuroblastoma-cells-against-a-comprehensive-small-molecule-kinase-inhibitor-library-to-identify-agents-for-future-therapeutic-studies
#14
Anjali Singh, Vanessa Meier-Stephenson, Aarthi Jayanthan, Aru Narendran
Solid tumors represent one of the most widespread causes of death in children across the world. Neuroblastoma (NB) constitutes about 8% of all childhood tumors, yet accounts for more than 15% of death, with an unacceptable overall survival rate. Despite the current multimodal therapeutic approaches involving surgery, radiation, chemotherapy with myeloablative therapy and hematopoietic stem cell rescue, there is growing realization of the limitations of conventional agents to improve the outcome in high risk metastatic disease...
November 22, 2016: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/27875633/design-synthesis-and-evaluation-of-dasatinib-amino-acid-and-dasatinib-fatty-acid-conjugates-as-protein-tyrosine-kinase-inhibitors
#15
Rakesh K Tiwari, Alex Brown, Neda Sadeghiani, Amir Nasrolahi Shirazi, Jared Bolton, Amanda Tse, Gennady Verkhivker, Keykavous Parang, Gongqin Sun
Derivatives of the tyrosine kinase inhibitor dasatinib were synthesized by esterification with 25 carboxylic acids, including amino acids and fatty acids, thereby extending the drug to interact with more diverse sites and to improve specificity. The dasatinib-l-arginine derivative (Das-R, 7) was found to be the most potent of the inhibitors tested, with IC50 values of 4.4, <0.25, and <0.45 nm against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src, belonged to compound 18 (Das-C10 ) with an IC50 value of 3...
November 22, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27872592/a-pyrazolo-3-4-d-pyrimidine-compound-reduces-cell-viability-and-induces-apoptosis-in-different-hematological-malignancies
#16
Ilaria Laurenzana, Antonella Caivano, Francesco La Rocca, Stefania Trino, Luciana De Luca, Francesca D'Alessio, Silvia Schenone, Geppino Falco, Maurizio Botta, Luigi Del Vecchio, Pellegrino Musto
Molecular targeted therapies are based upon drugs acting on tumors by interfering with specific targets involved in growth and spread of cancer. Many targeted therapies were approved by Food and Drug Administration as standard treatment, others were introduced into preclinical or clinical studies on hematological malignancies (HMs). The development of drug-resistance in some HMs and the lack of effective treatments in other ones emphasized the need for searching new molecular targets and therapeutic agents...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27872192/the-chromatin-assembly-factor-complex-1-caf1-and-5-azacytidine-5-azac-affect-cell-motility-in-src-transformed-human-epithelial-cells
#17
Akinori Endo, Tony Ly, Raffaella Pippa, Dalila Bensaddek, Armel Nicolas, Angus I Lamond
Tumor invasion into surrounding stromal tissue is a hallmark of high-grade, metastatic cancers. Oncogenic transformation of human epithelial cells in culture can be triggered by activation of v-Src kinase, resulting in increased cell motility, invasiveness and tumorigenicity and provides a valuable model for studying how changes in gene expression cause cancer phenotypes. Here, we show that epithelial cells transformed by activated Src show increased levels of DNA methylation and that the methylation inhibitor, 5-AzaC, potently blocks the increased cell motility and invasiveness induced by Src activation...
November 21, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27871934/v-src-induced-nuclear-localization-of-yap-is-involved-in-multipolar-spindle-formation-in-tetraploid-cells
#18
Keiko Kakae, Masayoshi Ikeuchi, Takahisa Kuga, Youhei Saito, Naoto Yamaguchi, Yuji Nakayama
The protein-tyrosine kinase, c-Src, is involved in a variety of signaling events, including cell division. We have reported that v-Src, which is a mutant variant of the cellular proto-oncogene, c-Src, causes delocalization of Aurora B kinase, resulting in a furrow regression in cytokinesis and the generation of multinucleated cells. However, the effect of v-Src on mitotic spindle formation is unknown. Here we show that v-Src-expressing HCT116 and NIH3T3 cells undergo abnormal cell division, in which cells separate into more than two cells...
November 18, 2016: Cellular Signalling
https://www.readbyqxmd.com/read/27866972/letrozole-regulates-actin-cytoskeleton-polymerization-dynamics-in-a-src-1-dependent-manner-in-the-hippocampus-of-mice
#19
Yangang Zhao, Yanlan Yu, Yuanyuan Zhang, Li He, Linli Qiu, Jikai Zhao, Mengying Liu, Jiqiang Zhang
In the hippocampus, local estrogens (E2) derived from testosterone that is catalyzed by aromatase play important roles in the regulation of hippocampal neural plasticity, but the underlying mechanisms remain unclear. The actin cytoskeleton contributes greatly to hippocampal synaptic plasticity; however, whether it is regulated by local E2 and the related mechanisms remain to be elucidated. In this study, we first examined the postnatal developmental profiles of hippocampal aromatase and specific proteins responsible for actin cytoskeleton dynamics...
November 17, 2016: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27835901/mutational-activation-of-braf-confers-sensitivity-to-transforming-growth-factor-beta-inhibitors-in-human-cancer-cells
#20
Lindsay C Spender, G John Ferguson, Sijia Liu, Chao Cui, Maria Romina Girotti, Gary Sibbet, Ellen B Higgs, Morven K Shuttleworth, Tom Hamilton, Paul Lorigan, Michael Weller, David F Vincent, Owen J Sansom, Margaret Frame, Peter Ten Dijke, Richard Marais, Gareth J Inman
Recent data implicate elevated transforming growth factor-β (TGFβ) signalling in BRAF inhibitor drug-resistance mechanisms, but the potential for targeting TGFβ signalling in cases of advanced melanoma has not been investigated. We show that mutant BRAFV600E confers an intrinsic dependence on TGFβ/TGFβ receptor 1 (TGFBR1) signalling for clonogenicity of murine melanocytes. Pharmacological inhibition of the TGFBR1 blocked the clonogenicity of human mutant BRAF melanoma cells through SMAD4-independent inhibition of mitosis, and also inhibited metastasis in xenografted zebrafish...
November 9, 2016: Oncotarget
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