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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 of 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...
November 29, 2017: Neurobiology of Disease
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...
November 27, 2017: Neuropharmacology
Ludiane Gauthier, Stephanie 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 αEβ7 (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...
October 11, 2017: Cancer Research
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
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
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
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
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...
June 13, 2017: Biological Psychiatry
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
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
Mossa Gardaneh, Sahar Shojaei, Ahmad Kaviani, Babak Behnam
We investigated the role of glial cell line-derived neurotrophic factor (GDNF) in compensating trastuzumab (TZMB)-induced apoptosis in HER2(+) breast cancer (BC) cells using xenograft tumors. We generated BC xenografts in nude mice using samples from three patients selected based on their HER2 status and response to TZMB therapy. TZMB treatment resulted in shrinkage of the HER2(+) TZMB-sensitive xenograft tumor but not the HER2(-) or HER2(+) TZMB-resistant ones. GDNF neutralized TZMB activity and induced growth in all tumors...
April 2017: Breast Cancer Research and Treatment
Jiaming Chen, Ying Peng, Jiang Zheng
Saracatinib is a highly selective Src kinase inhibitor against all Src kinase family members and has demonstrated anticancer effects in preclinical models. Unfortunately, it has shown multiple adverse effects during its clinical trials, along with time-dependent inhibition of P450 enzymes. The major objective of this study was to identify reactive metabolites of saracatinib in vitro and in vivo. Four oxidative metabolites (M1-M4) were detected in rat and human liver microsomal incubation systems after exposure to saracatinib...
November 21, 2016: Chemical Research in Toxicology
I Nakachi, B A Helfrich, M A Spillman, E A Mickler, C J Olson, J L Rice, C D Coldren, L E Heasley, M W Geraci, R S Stearman
Src kinase is recognized as a key target for molecular cancer therapy. However, methods to efficiently select patients responsive to Src inhibitors are lacking. We explored the sensitivity of ovarian cancer cell lines to the Src kinase inhibitor saracatinib to identify predictive markers of drug sensitivity using gene microarrays. Pituitary tumor transforming gene 1 (PTTG1) was selected as a potential biomarker as mRNA levels were correlated with saracatinib resistance, as well as higher PTTG1 protein expression...
December 2016: Clinical and Translational Science
Lingfei Wang, Xiaojie Yu, Jian Dong, Yanchun Meng, Yang Yang, Huajing Wang, Chao Wang, Yajun Zhang, Yirong Zhao, Jian Zhao, Hao Wang, Cuihua Lu, Bohua Li
Despite of the effectiveness of the anti-ErbB2 humanized antibody trastuzumab, trastuzumab resistance emerges as a major and common clinical problem. Thus, circumventing trastuzumab resistance has become an urgent need. Recently, Src inhibitor saracatinib has drawn great attention for its key role in trastuzumab response. As shown in our previous study, H2-18, an anti-ErbB2 antibody, could potently induce programmed cell death (PCD) in trastuzumab-resistant breast cancer cells. Here we combined H2-18 and a Src inhibitor, saracatinib, and studied the antitumor activity of this drug combination in trastuzumab-resistant breast cancer cell lines...
October 21, 2016: Biochemical and Biophysical Research Communications
Martina Tilio, Valentina Gambini, Junbiao Wang, Chiara Garulli, Cristina Kalogris, Cristina Andreani, Caterina Bartolacci, Maria Elexpuru Zabaleta, Lucia Pietrella, Albana Hysi, Manuela Iezzi, Barbara Belletti, Fiorenza Orlando, Mauro Provinciali, Roberta Galeazzi, Cristina Marchini, Augusto Amici
HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Δ16HER2 splice variant commonly coexpressed with HER2 and identified as a clinically important HER2 molecular alteration promoting aggressive metastatic breast cancer. Consistently, mice transgenic for the human Δ16HER2 isoform (Δ16HER2 mice) develop invasive mammary carcinomas with early onset and 100% penetrance. The present study provides preclinical evidence that Δ16HER2 expression confers de novo resistance to standard anti-HER2-therapies such as Lapatinib and acquired resistance to the selective Src inhibitor Saracatinib in breast cancer...
October 10, 2016: Cancer Letters
Ju Xiong, Jin-Sheng Wu, Shan-Shan Mao, Xiang-Nan Yu, Xiao-Xi Huang
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Src is involved in multiple processes of cancer metastasis; however, its significance in HCC is not well defined. In the present study, overexpression of Src phosphorylation (Y416) was observed in the highly metastatic MHCC97H cell line; additionally, through inhibition of Src kinase activation, HCC cell proliferation, migration, invasion and colony formation were significantly reduced in vitro. Tumour growth was not affected in the orthotopic xenograft HCC model, but the metastasic potential was inhibited as revealed by reduced lung metastasic foci after administration of saracatinib...
September 2016: Oncology Reports
Sacha I Rothschild, Oliver Gautschi, Jasmin Batliner, Mathias Gugger, Martin F Fey, Mario P Tschan
OBJECTIVES: Src tyrosine kinase inhibitors (TKIs) significantly inhibit cell migration and invasion in lung cancer cell lines with minor cytotoxic effects. In clinical trials, however, they show modest activity in combination with chemotherapeutic agents. Possible resistance mechanisms include the induction of cytoprotective autophagy upon Src inhibition. Autophagy is a cellular recycling process that allows cell survival in response to a variety of stress stimuli including responses to various treatments...
May 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Roy Heusschen, Joséphine Muller, Marilène Binsfeld, Caroline Marty, Erwan Plougonven, Sophie Dubois, Nadia Mahli, Karen Moermans, Geert Carmeliet, Angélique Léonard, Frédéric Baron, Yves Beguin, Eline Menu, Martine Cohen-Solal, Jo Caers
Multiple myeloma (MM)-associated osteolytic bone disease is a major cause of morbidity and mortality in MM patients and the development of new therapeutic strategies is of great interest. The proto-oncogene SRC is an attractive target for such a strategy. In the current study, we investigated the effect of treatment with the SRC inhibitor saracatinib (AZD0530) on osteoclast and osteoblast differentiation and function, and on the development of MM and its associated bone disease in the 5TGM.1 and 5T2MM murine MM models...
May 24, 2016: Oncotarget
Milena De Felice, Daniel Lambert, Ingunn Holen, K Jane Escott, David Andrew
BACKGROUND: Bone metastases occur frequently in advanced breast, lung, and prostate cancer, with approximately 70% of patients affected. Pain is a major symptom of bone metastases, and current treatments may be inadequate or have unacceptable side effects. The mechanisms that drive cancer-induced bone pain are not fully understood; however, it is known that there is sensitization of both peripheral bone afferents and central spinal circuits. It is well established that the N-methyl-D-aspartate receptor plays a major role in the pathophysiology of pain hypersensitivity...
2016: Molecular Pain
Antonia K Roseweir, Tahir Qayyum, Zhi Lim, Rachel Hammond, Alasdair I MacDonald, Sioban Fraser, Grenville M Oades, Michael Aitchison, Robert J Jones, Joanne Edwards
BACKGROUND: 8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50%. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). METHODS: SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up...
March 16, 2016: BMC Cancer
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