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https://www.readbyqxmd.com/read/29614307/lc-ms-ms-reveals-the-formation-of-reactive-ortho-quinone-and-iminium-intermediates-in-saracatinib-metabolism-phase-i-metabolic-profiling
#1
Mohamed W Attwa, Adnan A Kadi, Hany W Darwish, Haitham Alrabiah
Saracatinib (AZD-0530) is a drug under clinical trials that developed by AstraZeneca. It is considered a dual kinase inhibitor, with selective actions as a Src inhibitor and a Bcr-Abl tyrosine-kinase inhibitor. Saracatinib chemical structure contains N-methyl piperazine group and 1,3 benzodioxole group. N-methyl piperazine group that can be bioactivated to form iminium intermediates which can be captured by KCN. 1,3-Benzodioxole group can be bioactivated to form ortho-quinone intermediate that can be conjugated with GSH...
March 31, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29601121/pai-1-induces-src-inhibitor-resistance-via-ccl5-in-her2-positive-breast-cancer-cells
#2
Hehui Fang, Juan Jin, Doudou Huang, Fang Yang, Xiaoxiang Guan
Tyrosine kinase Src is overexpressed and activated in various tumors, including breast cancer, and is supposed to promote cancer formation and development. Src inhibitors are recently developed and have shown efficacy in breast cancer as single agent or in combination with anti-HER2 antibodies or chemotherapy. Unfortunately, the potency of Src inhibitor is limited by the development of drug resistance. In our study, we established a Src inhibitor saracatinib-resistant breast cancer cell line (SKBR-3/SI) for the first time and by evaluating mRNA expression profile, we first found that plasminogen activator inhibitor-1 (PAI-1) was upregulated in saracatinib-resistant cells compared to the parent cells...
March 30, 2018: Cancer Science
https://www.readbyqxmd.com/read/29555825/tyrosine-kinase-fyn-promotes-osteoarthritis-by-activating-the-%C3%AE-catenin-pathway
#3
Kai Li, Yue Zhang, Yuwei Zhang, Wenqing Jiang, Junhui Shen, Song Xu, Daozhang Cai, Jie Shen, Bin Huang, Mangmang Li, Qiancheng Song, Yu Jiang, Anling Liu, Xiaochun Bai
OBJECTIVES: To investigate the role of tyrosine kinase Fyn in the development of osteoarthritis (OA) and the underlying mechanisms, and to define whether targeting Fyn could prevent OA in mice. METHODS: Cartilage samples from normal and aged mice were analysed with proteome-wide screening. Fyn expression was examined with immunofluorescence in human and age-dependent or experimental mouse OA cartilage samples. Experimental OA in Fyn-knockout mice was induced by destabilisation of the medial meniscus...
March 19, 2018: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/29550144/mir-19b-3p-inhibits-breast-cancer-cell-proliferation-and-reverses-saracatinib-resistance-by-regulating-pi3k-akt-pathway
#4
Juan Jin, Zijia Sun, Fang Yang, Lin Tang, Weiwei Chen, Xiaoxiang Guan
Breast cancer arises as the most frequent malignancy, and causes the majority of cancer death among females worldwide. Src is a tyrosine kinase identified as the product of the proto-oncogene and is supposed to promote cancer development and metastasis. Src inhibitors are recently developed and have shown efficacy in breast cancer. Increasing evidences suggest that aberrant expression of miRNAs is involved in cancer development and drug resistance. Identifying miRNAs associated with drug resistance may enhance the sensitivity of targeted therapies, including Src inhibitors...
March 14, 2018: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29535838/targeting-loss-of-the-hippo-signaling-pathway-in-nf2-deficient-papillary-kidney-cancers
#5
Carole Sourbier, Pei-Jyun Liao, Christopher J Ricketts, Darmood Wei, Youfeng Yang, Sarah M Baranes, Benjamin K Gibbs, Lernik Ohanjanian, L Spencer Krane, Bradley T Scroggins, J Keith Killian, Ming-Hui Wei, Toshiki Kijima, Paul S Meltzer, Deborah E Citrin, Len Neckers, Cathy D Vocke, W Marston Linehan
Papillary renal cell carcinomas (PRCC) are a histologically and genetically heterogeneous group of tumors that represent 15-20% of all kidney neoplasms and may require diverse therapeutic approaches. Alteration of the NF2 tumor suppressor gene, encoding a key regulator of the Hippo signaling pathway, is observed in 22.5% of PRCC. The Hippo signaling pathway controls cell proliferation by regulating the transcriptional activity of Yes-Associated Protein, YAP1. Loss of NF2 results in aberrant YAP1 activation...
February 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29535432/saracatinib-impairs-maintenance-of-human-t-all-by-targeting-the-lck-tyrosine-kinase-in-cells-displaying-high-level-of-lipid-rafts
#6
Anne Buffière, Théo Accogli, Laetitia Saint-Paul, Géraldine Lucchi, Benjamin Uzan, Paola Ballerini, Jean-Noël Bastie, Laurent Delva, Françoise Pflumio, Ronan Quéré
No abstract text is available yet for this article.
February 28, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29530864/substrate-selectivity-check-of-the-ergothioneine-transporter
#7
Julia Tschirka, Madlen Kreisor, Janina Betz, Dirk Grundemann
The candidate vitamin ergothioneine (ET) is a unique antioxidant. Expression of the ergothioneine transporter (ETT) (gene symbol SLC22A4) in distinct cells is thought to signal intracellular ET activity, since we have previously shown that the ETT is highly selective for ET. Unfortunately, some continue to hold the ETT as a relevant drug transporter, using the misleading functional name OCTN1, novel organic cation transporter. The present study was provoked by 2 recent reports in which new ETT substrates were declared...
March 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29435137/activation-of-mapk-signalling-results-in-resistance-to-saracatinib-azd0530-in-ovarian-cancer
#8
Niamh McGivern, Aya El-Helali, Paul Mullan, Iain A McNeish, D Paul Harkin, Richard D Kennedy, Nuala McCabe
SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29401603/hepatitis-b-virus-core-protein-promotes-hepatocarcinogenesis-by-enhancing-src-expression-and-activating-the-src-pi3k-akt-pathway
#9
Wei Liu, Teng-Fei Guo, Zhen-Tang Jing, Zhi Yang, Lei Liu, Yuan-Ping Yang, Xu Lin, Qiao-Yun Tong
Hepatitis B virus core protein (HBc) is expressed preferentially in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). HBc can function as an oncogene arising from its gene regulatory properties, but how it contributes functionally to hepatocarcinogenesis remains unclear. In this study, we determined the molecular and functional roles of HBc during HBV-associated hepatocellular tumorigenesis. HBc increased tumor formation of hepatoma cells. Moreover, expression of HBc specifically promoted proliferation of hepatoma cells in vitro...
January 17, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29318780/the-synergistic-role-of-atp-dependent-drug-efflux-pump-and-focal-adhesion-signaling-pathways-in-vinorelbine-resistance-in-lung-cancer
#10
Takao Nakanishi, Toshi Menju, Shigeto Nishikawa, Koji Takahashi, Ryo Miyata, Kei Shikuma, Terumasa Sowa, Naoto Imamura, Masatsugu Hamaji, Hideki Motoyama, Kyoko Hijiya, Akihiro Aoyama, Toshihiko Sato, Toyofumi F Chen-Yoshikawa, Makoto Sonobe, Hiroshi Date
The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non-small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB-resistant (VR) lung cancer cells (NCI-H1299 and A549) and examined its transcriptional changes, protein expressions, and activations...
February 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29197620/role-of-the-fyn-pkc%C3%AE-signaling-in-se-induced-neuroinflammation-and-epileptogenesis-in-experimental-models-of-temporal-lobe-epilepsy
#11
Shaunik Sharma, Steven Carlson, Sreekanth Puttachary, Souvarish Sarkar, Lucas Showman, Marson Putra, Anumantha G Kanthasamy, Thimmasettappa Thippeswamy
Status epilepticus (SE) induces neuroinflammation and epileptogenesis, but the mechanisms are not yet fully delineated. The Fyn, a non-receptor Src family tyrosine kinase (SFK), and its immediate downstream target, PKCδ are emerging as potential mediators of neuroinflammation. In order to first determine the role of Fyn kinase signaling in SE, we tested the efficacy of a SFK inhibitor, saracatinib (25mg/kg, oral) in C57BL/6J mouse kainate model of acute seizures. Saracatinib pretreatment dampened SE severity and completely prevented mortality...
February 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29191754/disease-modifying-benefit-of-fyn-blockade-persists-after-washout-in-mouse-alzheimer-s-model
#12
Levi M Smith, Rong Zhu, Stephen M Strittmatter
Alzheimer's disease remains without a disease-modifying therapy that improves symptoms after therapy withdrawal. Because no investigational agents have demonstrated disease-modifying effects clinically, we tested whether the Fyn inhibitor, saracatinib, provides persistent improvement in a transgenic model. Aged APPswe/PS1ΔE9 mice were treated with saracatinib or memantine for 4 weeks and spatial memory improved to control levels. After drug washout, there was sustained rescue of both memory function and synapse density by saracatinib, but a loss of benefit from memantine...
March 1, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29021139/paxillin-binding-to-the-cytoplasmic-domain-of-cd103-promotes-cell-adhesion-and-effector-functions-for-cd8-resident-memory-t-cells-in-tumors
#13
Ludiane Gauthier, Stéphanie Corgnac, Marie Boutet, Gwendoline Gros, Pierre Validire, Georges Bismuth, Fathia Mami-Chouaib
CD8+ /CD103+ tissue-resident memory T cells (TRM cells) accumulate in several human solid tumors, where they have been associated with a favorable prognosis. However, the role of CD103, the α subunit of the integrin αE β7 (also known as CD103), in the retention and functions of these TRM is undefined. In this report, we investigated the role of CD103 cytoplasmic domain and the focal adhesion-associated protein paxillin (Pxn) in downstream signaling and functional activities triggered through αE /CD103 chain...
December 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28840468/the-kinase-fyn-as-a-novel-intermediate-in-l-dopa-induced-dyskinesia-in-parkinson-s-disease
#14
Sara Sanz-Blasco, Melina P Bordone, Ana Damianich, Gimena Gomez, M Alejandra Bernardi, Luciana Isaja, Irene R Taravini, Diane P Hanger, M Elena Avale, Oscar S Gershanik, Juan E Ferrario
Dopamine replacement therapy with L-DOPA is the treatment of choice for Parkinson's disease; however, its long-term use is frequently associated with L-DOPA-induced dyskinesia (LID). Many molecules have been implicated in the development of LID, and several of these have been proposed as potential therapeutic targets. However, to date, none of these molecules have demonstrated full clinical efficacy, either because they lie downstream of dopaminergic signaling, or due to adverse side effects. Therefore, discovering new strategies to reduce LID in Parkinson's disease remains a major challenge...
August 24, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28838952/cd55-regulates-self-renewal-and-cisplatin-resistance-in-endometrioid-tumors
#15
Caner Saygin, Andrew Wiechert, Vinay S Rao, Ravi Alluri, Elizabeth Connor, Praveena S Thiagarajan, James S Hale, Yan Li, Anastasia Chumakova, Awad Jarrar, Yvonne Parker, Daniel J Lindner, Anil Belur Nagaraj, J Julie Kim, Analisa DiFeo, Fadi W Abdul-Karim, Chad Michener, Peter G Rose, Robert DeBernardo, Haider Mahdi, Keith R McCrae, Feng Lin, Justin D Lathia, Ofer Reizes
Effective targeting of cancer stem cells (CSCs) requires neutralization of self-renewal and chemoresistance, but these phenotypes are often regulated by distinct molecular mechanisms. Here we report the ability to target both of these phenotypes via CD55, an intrinsic cell surface complement inhibitor, which was identified in a comparative analysis between CSCs and non-CSCs in endometrioid cancer models. In this context, CD55 functions in a complement-independent manner and required lipid raft localization for CSC maintenance and cisplatin resistance...
September 4, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28830985/characterization-of-in-vivo-resistance-to-osimertinib-and-jnj-61186372-an-egfr-met-bispecific-antibody-reveals-unique-and-consensus-mechanisms-of-resistance
#16
Kristina B Emdal, Antje Dittmann, Raven J Reddy, Rebecca S Lescarbeau, Sheri L Moores, Sylvie Laquerre, Forest M White
Approximately 10% of non-small cell lung cancer (NSCLC) patients in the United States and 40% of NSCLC patients in Asia have activating epidermal growth factor receptor (EGFR) mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be cotargeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival...
November 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28775147/combination-therapy-with-c-met-and-src-inhibitors-induces-caspase-dependent-apoptosis-of-merlin-deficient-schwann-cells-and-suppresses-growth-of-schwannoma-cells
#17
Marisa A Fuse, Stephani Klingeman Plati, Sarah S Burns, Christine T Dinh, Olena Bracho, Denise Yan, Rahul Mittal, Rulong Shen, Julia N Soulakova, Alicja J Copik, Xue Zhong Liu, Fred F Telischi, Long-Sheng Chang, Maria Clara Franco, Cristina Fernandez-Valle
Neurofibromatosis type 2 (NF2) is a nervous system tumor disorder caused by inactivation of the merlin tumor suppressor encoded by the NF2 gene. Bilateral vestibular schwannomas (VS) are a diagnostic hallmark of NF2. Mainstream treatment options for NF2-associated tumors have been limited to surgery and radiotherapy; however, off-label uses of targeted molecular therapies are becoming increasingly common. Here we investigated drugs targeting two kinases activated in NF2-associated schwannomas, c-Met and Src...
August 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28709498/targeting-fyn-kinase-in-alzheimer-s-disease
#18
REVIEW
Haakon B Nygaard
The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD...
February 15, 2018: Biological Psychiatry
https://www.readbyqxmd.com/read/28561330/impaired-activity-of-adherens-junctions-contributes-to-endothelial-dilator-dysfunction-in-ageing-rat-arteries
#19
Fumin Chang, Sheila Flavahan, Nicholas A Flavahan
KEY POINTS: Ageing-induced endothelial dysfunction contributes to organ dysfunction and progression of cardiovascular disease. VE-cadherin clustering at adherens junctions promotes protective endothelial functions, including endothelium-dependent dilatation. Ageing increased internalization and degradation of VE-cadherin, resulting in impaired activity of adherens junctions. Inhibition of VE-cadherin clustering at adherens junctions (function-blocking antibody; FBA) reduced endothelial dilatation in young arteries but did not affect the already impaired dilatation in old arteries...
August 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28455521/importance-of-the-novel-organic-cation-transporter-1-for-tyrosine-kinase-inhibition-by-saracatinib-in-rheumatoid-arthritis-synovial-fibroblasts
#20
Saliha Harrach, Bayram Edemir, Christian Schmidt-Lauber, Thomas Pap, Jessica Bertrand, Giuliano Ciarimboli
Recent therapeutic approaches of rheumatoid arthritis (RA) address the use of small molecules such as tyrosine kinase inhibitors (TKIs). However, the TKIs developed to date have important side effects and/or scarce efficacy in inflammatory diseases such as RA. Since intracellular effective TKIs must enter the cell to reach their intracellular targets, here we investigated the interaction of the TKI saracatinib, a dual inhibitor of c-Src and c-Abl signaling, with transporters for organic cations as well as the role of these transporters for the biological effect of saracatinib in human RA-synovial fibroblasts (hRASF)...
April 28, 2017: Scientific Reports
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