Read by QxMD icon Read


Jiaming Chen, Ying Peng, Jiang Zheng
Saracatinib, is a highly selective Src kinase inhibitor against all Src kinase family members and has demonstrated anti-cancer 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...
October 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...
October 20, 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...
June 14, 2016: 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...
2016: BMC Cancer
Weibing Leng, Dezhi Li, Liang Chen, Hongwei Xia, Qiulin Tang, Baoqin Chen, Qiyong Gong, Fabao Gao, Feng Bi
Aberrant activation of the Src kinase is implicated in the development of a variety of human malignancies. However, it is almost impossible to monitor Src activity in an in vivo setting with current biochemical techniques. To facilitate the noninvasive investigation of the activity of Src kinase both in vitro and in vivo, we developed a genetically engineered, activatable bioluminescent reporter using split-luciferase complementation. The bioluminescence of this reporter can be used as a surrogate for Src activity in real time...
2016: Theranostics
Jaume Folch, Dmitry Petrov, Miren Ettcheto, Sonia Abad, Elena Sánchez-López, M Luisa García, Jordi Olloquequi, Carlos Beas-Zarate, Carme Auladell, Antoni Camins
Alzheimer's disease (AD) currently presents one of the biggest healthcare issues in the developed countries. There is no effective treatment capable of slowing down disease progression. In recent years the main focus of research on novel pharmacotherapies was based on the amyloidogenic hypothesis of AD, which posits that the beta amyloid (Aβ) peptide is chiefly responsible for cognitive impairment and neuronal death. The goal of such treatments is (a) to reduce Aβ production through the inhibition of β and γ secretase enzymes and (b) to promote dissolution of existing cerebral Aβ plaques...
2016: Neural Plasticity
T Powles, J Brown, J Larkin, R Jones, C Ralph, R Hawkins, S Chowdhury, E Boleti, A Bhal, K Fife, A Webb, S Crabb, T Geldart, R Hill, J Dunlop, P E Hall, D McLaren, C Ackerman, L Beltran, P Nathan
BACKGROUND: Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib. PATIENTS AND METHODS: Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study...
May 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Edwin M Posadas, Rafi S Ahmed, Theodore Karrison, Russell Z Szmulewitz, Peter H O'Donnell, James L Wade, James Shen, Murali Gururajan, Margarit Sievert, Walter M Stadler
BACKGROUND: Fyn is a kinase that is upregulated in a subset of metastatic castration-resistant prostate cancer. Saracatinib potently inhibits Fyn activation. We have noted a relationship between Fyn expression and directional motility, a cellular process related to metastasis. As such we hypothesized that treatment with saracatinib would increase the time required to develop new metastatic lesions. METHODS: Patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel were eligible for enrollment...
February 15, 2016: Prostate
Shalini Jain, Xiao Wang, Chia-Chi Chang, Catherine Ibarra-Drendall, Hai Wang, Qingling Zhang, Samuel W Brady, Ping Li, Hong Zhao, Jessica Dobbs, Matt Kyrish, Tomasz S Tkaczyk, Adrian Ambrose, Christopher Sistrunk, Banu K Arun, Rebecca Richards-Kortum, Wei Jia, Victoria L Seewaldt, Dihua Yu
Preventing breast cancer will require the development of targeted strategies that can effectively block disease progression. Tamoxifen and aromatase inhibitors are effective in addressing estrogen receptor-positive (ER(+)) breast cancer development, but estrogen receptor-negative (ER(-)) breast cancer remains an unmet challenge due to gaps in pathobiologic understanding. In this study, we used reverse-phase protein array to identify activation of Src kinase as an early signaling alteration in premalignant breast lesions of women who did not respond to tamoxifen, a widely used ER antagonist for hormonal therapy of breast cancer...
November 15, 2015: Cancer Research
Kian Ngiap Chua, Li Ren Kong, Wen Jing Sim, Hsien Chun Ng, Weijie Richard Ong, Jean Paul Thiery, Hung Huynh, Boon Cher Goh
Oncogenesis in non-small cell lung cancer (NSCLC) is regulated by a complex signal transduction network. Single-agent targeted therapy fails frequently due to treatment insensitivity and acquired resistance. In this study, we demonstrate that co-inhibition of the MAPK and SRC pathways using a PD0325901 and Saracatinib kinase inhibitor combination can abrogate tumor growth in NSCLC. PD0325901/Saracatinib at 0.25:1 combination was screened against a panel of 28 NSCLC cell lines and 68% of cell lines were found to be sensitive (IC50 < 2 μM) to this combination...
October 6, 2015: Oncotarget
Nan Wang, Dan Zhang, Gengyun Sun, Hong Zhang, Qinghai You, Min Shao, Yang Yue
BACKGROUND: Lipopolysaccharide (LPS) was shown to induce an increase in caveolin-1 (Cav-1) expression in endothelial cells; however, the mechanisms regarding this response and the consequences on caveolae-mediated transcellular transport have not been completely investigated. This study aims to investigate the role of LPS-induced Cav-1 phosphorylation in pulmonary microvascular permeability in pulmonary microvascular endothelial cells (PMVECs). METHODS: Rat PMVECs were isolated, cultured, and identified...
2015: Drug Design, Development and Therapy
Luigi Formisano, Valentina D'Amato, Alberto Servetto, Simona Brillante, Lucia Raimondo, Concetta Di Mauro, Roberta Marciano, Roberta Clara Orsini, Sandro Cosconati, Antonio Randazzo, Sarah J Parsons, Nunzia Montuori, Bianca Maria Veneziani, Sabino De Placido, Roberta Rosa, Roberto Bianco
Resistance to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, often related to Ras or secondary EGFR mutations, is a relevant clinical issue in Non-Small Cell Lung Cancer (NSCLC). Although Src TK has been involved in such resistance, clinical development of its inhibitors has been so far limited. To better define the molecular targets of the Src TKIs saracatinib, dasatinib and bosutinib, we used a variety of in vitro/in vivo studies. Kinase assays supported by docking analysis demonstrated that all the compounds directly inhibit EGFR TK variants...
September 22, 2015: Oncotarget
Chan Woo Kang, Kang Won Jang, Jinyoung Sohn, Sung-Moo Kim, Kyoung-Ho Pyo, Hwan Kim, Mi Ran Yun, Han Na Kang, Hye Ryun Kim, Sun Min Lim, Yong Wha Moon, Soonmyung Paik, Dae Joon Kim, Joo Hang Kim, Byoung Chul Cho
RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G0-G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells...
October 2015: Molecular Cancer Therapeutics
Quanchi Chen, Zifei Zhou, Liancheng Shan, Hui Zeng, Yingqi Hua, Zhengdong Cai
Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy...
July 2015: Oncology Letters
Wenzhi Li, Zhanyu Wang, Longmei Wang, Xiangfei He, Guangjian Wang, Hongjun Liu, Fengfu Guo, Zhong Wang, Gang Chen
To investigate the effect of different concentrations of inhibitors rapamycin, saracatinib, linsitinib and JNJ-38877605 on PC-3 cells with CCK-8 assay, respectively. PC-3 cells were incubated with different concentrations of rapamycin, saracatinib, linsitinib and JNJ-38877605, respectively, for 48 h at 37°C, the concentrations of rapamycin were 5 nM, 10 nM, 20 nM, 50 nM, 75 nM, 100 nM; Saracatinib: 0.125 nM, 0.25 nM, 0.5 nM, 1 nM, 2.5 nM, 5 nM; Linsitinib: 2 nM, 5 nM, 10 nM, 20 nM, 40 nM, 60 nM; JNJ-38877605: 0...
2015: International Journal of Clinical and Experimental Medicine
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"