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https://www.readbyqxmd.com/read/29776413/the-cxcr4-antagonist-plerixafor-amd3100-promotes-proliferation-of-ewing-sarcoma-cell-lines-in-vitro-and-activates-receptor-tyrosine-kinase-signaling
#1
Philipp Berning, Christiane Schaefer, Dagmar Clemens, Eberhard Korsching, Uta Dirksen, Jenny Potratz
BACKGROUND: The CXCR4 receptor antagonist plerixafor (AMD3100) is raising interest as an anti-cancer agent that disrupts the CXCL12-CXCR4 chemokine - receptor interaction between neoplastic cells and their microenvironment in tumor progression and metastasis. Here, we investigated plerixafor for anti-cancer activity in Ewing sarcoma, a rare and aggressive cancer of bone and soft tissues. METHODS: We used a variety of methods such as cell viability and migration assays, flow cytometry, phospho-tyrosine arrays and western blotting to determine plerixafor effects on five characterized Ewing sarcoma cell lines and a low-passage culture in vitro...
May 18, 2018: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/29776093/impact-of-hydrodynamic-interactions-on-protein-folding-rates-depends-on-temperature
#2
Fabio C Zegarra, Dirar Homouz, Yossi Eliaz, Andrei G Gasic, Margaret S Cheung
We investigated the impact of hydrodynamic interactions (HI) on protein folding using a coarse-grained model. The extent of the impact of hydrodynamic interactions, whether it accelerates, retards, or has no effect on protein folding, has been controversial. Together with a theoretical framework of the energy landscape theory (ELT) for protein folding that describes the dynamics of the collective motion with a single reaction coordinate across a folding barrier, we compared the kinetic effects of HI on the folding rates of two protein models that use a chain of single beads with distinctive topologies: a 64-residue α/β chymotrypsin inhibitor 2 (CI2) protein, and a 57-residue β-barrel α-spectrin Src-homology 3 domain (SH3) protein...
March 2018: Physical Review. E
https://www.readbyqxmd.com/read/29774100/differential-proteomic-profile-of-leukemic-cd34-progenitor-cells-from-chronic-myeloid-leukemia-patients
#3
Maria Rosaria Ricciardi, Valentina Salvestrini, Roberto Licchetta, Simone Mirabilii, Mattia Forcato, Gabriele Gugliotta, Simona Salati, Fausto Castagnetti, Gianantonio Rosti, Massimo Breccia, Giuliana Alimena, Rossella Manfredini, Silvio Bicciato, Roberto Massimo Lemoli, Agostino Tafuri
Chronic Myeloid Leukemia (CML) is a stem cell disease sustained by a rare population of quiescent cells which are to some extent resistant to tyrosine kinase inhibitors (TKIs). BCR-ABL oncogene activates multiple cross-talking signal transduction pathways (STP), such as RAS/MEK/ERK, PI3K/Akt, Wnt and STAT5, contributing to abnormal proliferation of clonal cells. From this perspective, the aim of this study was to analyze the expression and activation profile of STP involved in the mechanisms of cell proliferation/quiescence and survival of the progenitor CD34+ cells from chronic phase (CP) CML...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29773593/safety-and-efficacy-of-second-line-bosutinib-for-chronic-phase-chronic-myeloid-leukemia-over-a-five-year-period-final-results-of-a-phase-1-2-study
#4
Carlo Gambacorti-Passerini, Jorge E Cortes, Jeff H Lipton, Hagop M Kantarjian, Dong-Wook Kim, Philippe Schafhausen, Rocco Crescenzo, Nathalie Bardy-Bouxin, Mark Shapiro, Kay Noonan, Eric Leip, Liza DeAnnuntis, Tim H Brümmendorf, H Jean Khoury
Bosutinib is a Src/Abl tyrosine kinase inhibitor indicated for adults with newly-diagnosed Ph+ chronic myeloid leukemia or with resistant/intolerant disease. We report the final results of a phase 1/2 study of second-line bosutinib in chronic phase chronic myeloid leukemia patients after imatinib failure (n=284). Median follow-up and treatment durations were 54.8 (range, 0.6-96.3) and 25.6 (0.2&-96.3) months, respectively. At years 2 and 5, 54% and 40% of patients, respectively, remained on bosutinib. Cumulative major cytogenetic response and complete cytogenetic response rates (newly-attained or maintained from baseline) were 58% and 46%, respectively, by year 2 and 60% and 50% by year 5...
May 17, 2018: Haematologica
https://www.readbyqxmd.com/read/29769618/inhibitor-of-apoptosis-proteins-iaps-mediate-collagen-type-xi-alpha-1-driven-cisplatin-resistance-in-ovarian-cancer
#5
Miran Rada, Sameera Nallanthighal, Jennifer Cha, Kerry Ryan, Jessica Sage, Catherine Eldred, Maria Ullo, Sandra Orsulic, Dong-Joo Cheon
Although, cisplatin resistance is a major challenge in the treatment of ovarian cancer, the precise mechanisms underlying cisplatin resistance are not fully understood. Collagen type XI alpha 1 (COL11A1), a gene encoding a minor fibrillar collagen of the extracellular matrix, is identified as one of the most upregulated genes in cisplatin-resistant ovarian cancer and recurrent ovarian cancer. However, the exact functions of COL11A1 in cisplatin resistance are unknown. Here we demonstrate that COL11A1 binds to integrin α1β1 and discoidin domain receptor 2 (DDR2) and activates downstream signaling pathways to inhibit cisplatin-induced apoptosis in ovarian cancer cells...
May 17, 2018: Oncogene
https://www.readbyqxmd.com/read/29765553/acquired-resistance-to-everolimus-in-aromatase-inhibitor-resistant-breast-cancer
#6
Mariko Kimura, Toru Hanamura, Kouki Tsuboi, Yosuke Kaneko, Yuri Yamaguchi, Toshifumi Niwa, Kazutaka Narui, Itaru Endo, Shin-Ichi Hayashi
We previously reported the establishment of several types of long-term estrogen-depleted-resistant (EDR) cell lines from MCF-7 breast cancer cells. Type 1 EDR cells exhibited the best-studied mechanism of aromatase inhibitor (AI) resistance, in which estrogen receptor (ER) expression remained positive and PI3K signaling was upregulated. Type 2 EDR cells showed reduced ER activity and upregulated JNK-related signaling. The mTOR inhibitor everolimus reduced growth in cells similar to Type 1 EDR cells. The present study generated everolimus-resistant (EvR) cells from Types 1 and 2 EDR cells following long-term exposure to everolimus in vitro ...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29765321/brain-lipopolysaccharide-preconditioning-induced-gene-reprogramming-mediates-a-tolerance-state-in-electroconvulsive-shock-model-of-epilepsy
#7
Elham Amini, Mojtaba Golpich, Abdoreza S Farjam, Behnam Kamalidehghan, Zahurin Mohamed, Norlinah M Ibrahim, Abolhassan Ahmadiani, Azman A Raymond
There is increasing evidence pointing toward the role of inflammatory processes in epileptic seizures, and reciprocally, prolonged seizures induce more inflammation in the brain. In this regard, effective strategies to control epilepsy resulting from neuroinflammation could be targeted. Based on the available data, preconditioning (PC) with low dose lipopolysaccharide (LPS) through the regulation of the TLR4 signaling pathway provides neuroprotection against subsequent challenge with injury in the brain. To test this, we examined the effects of a single and chronic brain LPS PC, which is expected to lead to reduction of inflammation against epileptic seizures induced by electroconvulsive shock (ECS)...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29765318/utility-of-a-novel-three-dimensional-and-dynamic-3dd-cell-culture-system-for-pk-pd-studies-evaluation-of-a-triple-combination-therapy-at-overcoming-anti-her2-treatment-resistance-in-breast-cancer
#8
Anusha Ande, Tanaya R Vaidya, Bao N Tran, Michael Vicchiarelli, Ashley N Brown, Sihem Ait-Oudhia
Background: Emergence of Human epidermal growth factor receptor 2 (HER2) therapy resistance in HER2-positive (HER2+) breast cancer (BC) poses a major clinical challenge. Mechanisms of resistance include the over-activation of the PI3K/mTOR and Src pathways. This work aims to investigate a novel combination therapy that employs paclitaxel (PAC), a mitotic inhibitor, with everolimus (EVE), an mTOR inhibitor, and dasatinib (DAS), an Src kinase inhibitor, as a modality to overcome resistance. Methods: Static (two dimensional, 2D) and three-dimensional dynamic (3DD) cell culture studies were conducted using JIMT-1 cells, a HER2+ BC cell line refractory to HER2 therapies...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29765299/src-kinase-dependent-rapid-non-genomic-modulation-of-hippocampal-spinogenesis-induced-by-androgen-and-estrogen
#9
Mika Soma, Jonghyuk Kim, Asami Kato, Suguru Kawato
Dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from an axon terminal at the synapse. Memories are stored in synapses which consist of spines and presynapses. Rapid modulations of dendritic spines induced by hippocampal sex steroids, including dihydrotestosterone (DHT), testosterone (T), and estradiol (E2), are essential for synaptic plasticity. Molecular mechanisms underlying the rapid non-genomic modulation through synaptic receptors of androgen (AR) and estrogen (ER) as well as its downstream kinase signaling, however, have not been well understood...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29763550/selective-inhibition-of-the-myeloid-src-family-kinase-fgr-potently-suppresses-aml-cell-growth-in-vitro-and-in-vivo
#10
Mark C Weir, Sherry T Shu, Ravi K Patel, Sabine Hellwig, Li Chen, Li Tan, Nathanael S Gray, Thomas E Smithgall
Acute myelogenous leukemia (AML) is the most common hematologic malignancy in adults, and is often associated with constitutive tyrosine kinase signaling. These pathways involve the non-receptor tyrosine kinases Fes, Syk and the three Src-family kinases expressed in myeloid cells (Fgr, Hck, and Lyn). In this study, we report remarkable anti-AML efficacy of an N-phenylbenzamide kinase inhibitor, TL02-59. This compound potently suppressed the proliferation of bone marrow samples from twenty of twenty-six AML patients, with a striking correlation between inhibitor sensitivity and expression levels of the myeloid Src family kinases Fgr, Hck, and Lyn...
May 15, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29760707/the-yin-and-yang-of-tyrosine-kinase-inhibition-during-experimental-polymicrobial-sepsis
#11
Cassiano Felippe Gonçalves-de-Albuquerque, Ina Rohwedder, Adriana Ribeiro Silva, Alessandra Silveira Ferreira, Angela R M Kurz, Céline Cougoule, Sarah Klapproth, Tanja Eggersmann, Johnatas D Silva, Gisele Pena de Oliveira, Vera Luiza Capelozzi, Gabriel Gutfilen Schlesinger, Edlaine Rijo Costa, Rita de Cassia Elias Estrela Marins, Attila Mócsai, Isabelle Maridonneau-Parini, Barbara Walzog, Patricia Rieken Macedo Rocco, Markus Sperandio, Hugo Caire de Castro-Faria-Neto
Neutrophils are the first cells of our immune system to arrive at the site of inflammation. They release cytokines, e.g., chemokines, to attract further immune cells, but also actively start to phagocytose and kill pathogens. In the case of sepsis, this tightly regulated host defense mechanism can become uncontrolled and hyperactive resulting in severe organ damage. Currently, no effective therapy is available to fight sepsis; therefore, novel treatment targets that could prevent excessive inflammatory responses are warranted...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29754422/zeb1-mediated-vasculogenic-mimicry-formation-associates-with-epithelial-mesenchymal-transition-and-cancer-stem-cell-phenotypes-in-prostate-cancer
#12
Hua Wang, Bin Huang, Bai Mou Li, Kai Yuan Cao, Chen Qiang Mo, Shuang Jian Jiang, Jin Cheng Pan, Zong Ren Wang, Huan Yi Lin, Dao Hu Wang, Shao Peng Qiu
The zinc finger E-box-binding homeobox 1 (ZEB1) induced the epithelial-mesenchymal transition (EMT) and altered ZEB1 expression could lead to aggressive and cancer stem cell (CSC) phenotypes in various cancers. Tissue specimens from 96 prostate cancer patients were collected for immunohistochemistry and CD34/periodic acid-Schiff double staining. Prostate cancer cells were subjected to ZEB1 knockdown or overexpression and assessment of the effects on vasculogenic mimicry formation in vitro and in vivo. The underlying molecular events of ZEB1-induced vasculogenic mimicry formation in prostate cancer were then explored...
May 12, 2018: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29752758/src-type-tyrosine-kinase-p56lck-is-critical-for-thymic-stromal-lymphopoietin-induced-allergic-rhinitis
#13
Sun-Young Nam, Hee-Yun Kim, Na-Ra Han, Phil-Dong Moon, Joong-Saeng Cho, Hyung-Min Kim, Hyun-Ja Jeong
BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a regulator of mast cell-mediated allergic inflammatory reactions, but the manner in which TSLP contributes to allergic rhinitis (AR) remains unclear. OBJECTIVE: Here we sought to determine that TSLP plays a crucial role in AR by interacting with Src-type tyrosine kinase p56lck and STAT6 and promoting mast cells degranulation. METHODS: The effects of TSLP on mast cell degranulation and AR were analyzed in human mast cell line (HMC-1 cells), ovalbumin (OVA)-induced AR animal model, and human subjects...
May 12, 2018: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29751129/selective-inhibition-of-src-family-kinases-by-su6656-increases-bone-mass-by-uncoupling-bone-formation-from-resorption-in-mice
#14
Cyril Thouverey, Serge Ferrari, Joseph Caverzasio
Mice deficient in the non-receptor tyrosine kinase Src exhibit high bone mass due to impaired bone resorption and increased bone formation. Although several Src family kinase inhibitors inhibit bone resorption in vivo, they display variable effects on bone formation. SU6656 is a selective Src family kinase inhibitor with weaker activity towards the non-receptor tyrosine kinase Abl and receptor tyrosine kinases which are required for appropriate osteoblast proliferation, differentiation and function. Therefore, we sought to determine whether SU6656 could increase bone mass by inhibiting bone resorption and by stimulating bone formation, and to explore its mechanisms of action...
May 8, 2018: Bone
https://www.readbyqxmd.com/read/29740790/identification-of-inhibitors-synergizing-gemcitabine-sensitivity-in-the-squamous-subtype-of-pancreatic-ductal-adenocarcinoma-pdac
#15
Jia Lin Er, Pei Ni Goh, Chen Yuan Lee, Ying Jie Tan, Ling-Wei Hii, Chun Wai Mai, Felicia Fei-Lei Chung, Chee-Onn Leong
Pancreatic adenocarcinoma (PDAC) is a highly aggressive cancer with a high chance of recurrence, limited treatment options, and poor prognosis. A recent study has classified pancreatic cancers into four molecular subtypes: (1) squamous, (2) immunogenic, (3) pancreatic progenitor and (4) aberrantly differentiated endocrine exocrine. Among all the subtypes, the squamous subtype has the worst prognosis. This study aims to utilize large scale genomic datasets and computational systems biology to identify potential drugs targeting the squamous subtype of PDAC through combination therapy...
May 8, 2018: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/29739921/microrna-181a-promotes-angiogenesis-in-colorectal-cancer-by-targeting-srcin1-to-promote-the-src-vegf-signaling-pathway
#16
Wu Sun, Xiaojun Wang, Jialu Li, Chaoying You, Pan Lu, Huijin Feng, Yan Kong, Haiyang Zhang, Yanqing Liu, Ruihua Jiao, Xi Chen, Yi Ba
Colorectal cancer (CRC) is a very common metastatic tumor with active angiogenesis that requires active angiogenesis. Recently, increased microRNA-181a-5p (miR-181a) expression was found to be significantly associated with liver metastasis and poor outcome in CRC patients. In this study, the role of miR-181a in tumor angiogenesis was further investigated. Capillary tube formation assays were used to demonstrate the ability of miR-181a to promote tumor angiogenesis. Bioinformatics analyses identified SRC kinase signaling inhibitor 1 (SRCIN1) as a potential target of miR-181a...
April 19, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29739850/small-molecule-targeting-of-the-stat5-6-src-homology-2-sh2-domains-to-inhibit-allergic-airway-disease
#17
J Morgan Knight, Pijus Mandal, Pietro Morlacchi, Garbo Mak, Evan Li, Matthew Madison, Cameron Landers, Brandon Saxton, Ed Felix, Brian Gilbert, Joel Sederstrom, Atul Varadhachary, Melissa M Singh, Dev Chatterjee, David B Corry, John S McMurray
Asthma is a chronic inflammatory disease of the lungs and airways and one of the most burdensome of all chronic maladies. Previous studies have established that expression of experimental and human asthma requires the IL-4/IL-13/IL-4 receptor alpha (IL-4Rα) signaling pathway, which activates the transcription factor STAT6. However, no small molecules targeting this important pathway are currently in clinical development. To this end, using a preclinical asthma model, we sought to develop and test a small-molecule inhibitor of the Src homology 2 domains in mouse and human STAT6...
May 8, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29739809/application-of-physiologically-based-pharmacokinetic-modeling-in-understanding-bosutinib-drug-drug-interactions-importance-of-intestinal-p-glycoprotein
#18
Shinji Yamazaki, Cho-Ming Loi, Emi Kimoto, Chester Costales, Manthena V Varma
Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Ph+ chronic myelogenous leukemia at a clinically recommended dose of 500 mg once daily. Clinical results indicated that increases in bosutinib oral exposures were supra-proportional at the lower doses (50 to 200 mg) and approximately dose-proportional at the higher doses (200 to 600 mg). Bosutinib is a substrate of CYP3A4 and P-glycoprotein and exhibits pH-dependent solubility with moderate intestinal permeability...
May 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29739791/%C3%AE-np63%C3%AE-src-slug-signalling-axis-promotes-epithelial-to-mesenchymal-transition-in-squamous-cancers
#19
Kirtiman Srivastava, Adam Pickard, Stephanie G Craig, Gerard P Quinn, Shauna M Lambe, Jacqueline A James, Simon McDade, Dennis McCance
PURPOSE: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in  Head and Neck Squamous Cell Carcinoma (HNSCC) and its importance in tumour invasion. EXPERIMENTAL DESIGN: We use a 3D invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the Human Papilloma Virus-16, coupled with bioinformatics and immunohistochemical analysis of patient samples to investigate  the role played by EMT in invasion and identify effectors and upstream regulatory pathways...
May 8, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29739052/mechanism-comparison-of-gemcitabine-and-dasatinib-resistant-pancreatic-cancer-by-integrating-mrna-and-mirna-expression-profiles
#20
Zongjing Chen, Liang Zhao, Keqing Shi, Bicheng Chen
BACKGROUND: Pancreatic cancer is one of the most lethal cancers with limited treatment options. Gemcitabine has been the standard drug for patients with advanced pancreatic cancer. Dasatinib is a competitive inhibitor of Src kinase, which has shown promise in treatment of pancreatic cancer. Several studies have revealed the drug resistant mechanism of gemcitabine or dasatinib in human cancers; however, few reports focused on the different mechanisms of gemcitabine and dasatinib resistance in pancreatic cancer...
May 1, 2018: Clinical Laboratory
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