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PI3K inhibitor

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https://www.readbyqxmd.com/read/28528184/synergistic-antitumor-effect-of-nvp-bez235-and-cape-on-mda-mb-231-breast-cancer-cells
#1
Samira Torki, Amin Soltani, Hedayatollah Shirzad, Nafiseh Esmaeil, Mahdi Ghatrehsamani
Triple negative breast cancer (TNBC) is the most lethal and aggressive kind of breast cancer. Studies with TNBC cells suggest that tumor environmental cytokines such as Transforming Growth Factor β1 (TGF-β1) have important roles in tumors fate. In the present study, we aimed to investigate, the effect of phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway dual inhibitor, NVP-BEZ235 and Caffeic acid phenyl ester (CAPE) on TNBC cell line (MDA-MB-231), stimulated with TGF-β1 for 14days in vitro...
May 18, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28526744/combining-properties-of-different-classes-of-pi3k%C3%AE-inhibitors-to-understand-molecular-features-that-confer-selectivity
#2
Grace Q Gong, Jackie D Kendall, James Mj Dickson, Gordon W Rewcastle, Christina M Buchanan, William A Denny, Peter R Shepherd, Jack U Flanagan
Phosphoinositide 3-kinases (PI3K) are major regulators of many cellular functions, and hyperactivation of PI3K cell signalling pathways is a major target for anticancer drug discovery. PI3Kα is the isoform most implicated in cancer, and our aim is to selectively inhibit this isoform, which may be more beneficial than concurrent inhibition of all Class I PI3Ks. We have used structure-guided design to merge high selectivity and high affinity characteristics found in existing compounds. Molecular docking including the prediction of water-mediated interactions, was used to model interactions between the ligands and the PI3Kα affinity pocket...
May 19, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28526367/discovery-of-a-novel-aminopyrazine-series-as-selective-pi3k%C3%AE-inhibitors
#3
Bernard Barlaam, Sabina Cosulich, Martina Fitzek, Hervé Germain, Stephen Green, Lyndsey L Hanson, Craig S Harris, Urs Hancox, Kevin Hudson, Christine Lambert-van der Brempt, Maryannick Lamorlette, Françoise Magnien, Gilles Ouvry, Ken Page, Linette Ruston, Lara Ward, Bénédicte Delouvrié
We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kβ and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration...
May 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28524116/inhibition-of-autophagy-promotes-salinomycin-induced-apoptosis-via-reactive-oxygen-species-mediated-pi3k-akt-mtor-and-erk-p38-mapk-dependent-signaling-in-human-prostate-cancer-cells
#4
Kwang-Youn Kim, Kwang-Il Park, Sang-Hun Kim, Sun-Nyoung Yu, Sul-Gi Park, Young Woo Kim, Young-Kyo Seo, Jin-Yeul Ma, Soon-Cheol Ahn
Recently, the interplay between autophagy and apoptosis has become an important factor in chemotherapy for cancer treatment. Inhibition of autophagy may be an effective strategy to improve the treatment of chemo-resistant cancer by consistent exposure to chemotherapeutic drugs. However, no reports have clearly elucidated the underlying mechanisms. Therefore, in this study, we assessed whether salinomycin, a promising anticancer drug, induces apoptosis and elucidated potential antitumor mechanisms in chemo-resistant prostate cancer cells...
May 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28522751/targeting-fbw7-as-a-strategy-to-overcome-resistance-to-targeted-therapy-in-non-small-cell-lung-cancer
#5
Mingxiang Ye, Yong Zhang, Xinxin Zhang, Jian-Bin Zhang, Pengyu Jing, Liang Cao, Nan Li, Xia Li, Libo Yao, Jian Zhang, Jian Zhang
Inhibition of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) signaling is highly effective in a subgroup of non-small cell lung cancer (NSCLC) patients with distinct clinicopathological features. However, resistance to EGFR and ALK inhibitors inevitably occurs, and the molecular mechanism underlying resistance is not fully understood. In this study, we report a PI3K/Akt- and MEK/Erk-independent resistance mechanism by which loss of the E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) leads to targeted therapy resistance via stabilization of anti-apoptotic protein MCL-1...
May 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28521397/regulation-of-angiogenic-factors-by-the-pi3k-akt-pathway-in-a549-lung-cancer-cells-under-hypoxic-conditions
#6
Youbang Xie, Yali Qi, Yanmiao Zhang, Jiayi Chen, Tianyi Wu, Yuhai Gu
The aim of the present study was to investigate the influence of hypoxia and PI3K inhibition on angiogenic factors in A549 lung cancer cells. A549 cells were treated with the PI3K inhibitor LY294002 under normoxic and hypoxic conditions. Untreated cells were used as the control group and those treated by the inhibitor, as the suppression group. The cells were further divided based on normoxic or hypoxic conditions and named: Normoxic control group, normoxic suppression group, hypoxic control group and hypoxic suppression group...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28521298/insulin-like-growth-factor-2-axis-supports-the-serum-independent-growth-of-malignant-rhabdoid-tumor-and-is-activated-by-microenvironment-stress
#7
Ting Li, Jin Wang, Pengfei Liu, Jiadong Chi, Han Yan, Lei Lei, Zexing Li, Bing Yang, Xi Wang
Malignant rhabdoid tumors (MRTs) are rare, lethal, pediatric tumors predominantly found in the kidney, brain and soft tissues. MRTs are driven by loss of tumor suppressor SNF5/INI1/SMARCB1/BAF47. The prognosis of MRT is poor using currently available treatments, so new treatment targets need to be identified to expand treatment options for patients experiencing chemotherapy resistance. The growth hormone insulin-like growth factor 2 (IGF2) signaling pathway is a promising target to overcome drug resistance in many cancers...
May 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28515443/development-of-a-whole-organism-platform-for-phenotype-based-analysis-of-igf1r-pi3k-akt-tor-action
#8
Chengdong Liu, Wei Dai, Yan Bai, Changfeng Chi, Yi Xin, Gen He, Kangsen Mai, Cunming Duan
Aberrant regulation of the insulin-like growth factor (IGF)/insulin (IIS)-PI3K-AKT-TOR signaling pathway is linked to major human diseases, and key components of this pathway are targets for therapeutic intervention. Current assays are molecular target- or cell culture-based platforms. Due to the great in vivo complexities inherited in this pathway, there is an unmet need for whole organism based assays. Here we report the development of a zebrafish transgenic line, Tg(igfbp5a:GFP), which faithfully reports the mitotic action of IGF1R-PI3K-Akt-Tor signaling in epithelial cells in real-time...
May 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28515318/molecular-mechanism-of-activation-of-class-ia-phosphoinositide-3-kinases-pi3ks-by-membrane-localized-hras
#9
Braden D Siempelkamp, Manoj K Rathinaswamy, Meredith L Jenkins, John E Burke
Class IA PI3Ks are involved in the generation of the key lipid signaling molecule phosphatidylinositol 3,4,5-trisphosphate (PIP3), and inappropriate activation of this pathway is implicated in a multitude of human diseases, including cancer, inflammation, and primary immunodeficiencies. Class IA PI3Ks are activated downstream of the Ras superfamily of GTPases, and Ras-PI3K interaction plays a key role in promoting tumor formation and maintenance in Ras-driven tumors. Investigating the detailed molecular events in the Ras-PI3K interaction has been challenging because it occurs on a membrane surface...
May 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28514770/mm-bmscs-induce-na%C3%A3-ve-cd4-t-lymphocytes-dysfunction-through-fibroblast-activation-protein-%C3%AE
#10
Xiaofei Wu, Yadan Wang, Jian Xu, Ting Luo, Jun Deng, Yu Hu
BACKGROUND: The tumor microenvironment plays a major role in multiple myelomas (MM). MM-BMSCs (bone marrow mesenchymal stromal cells) can support tumor growth and immune surveillance escape. On the other hand, fibroblast activation protein α, expressed by cancer stroma cells including BMSCs, has been shown to potentiate epithelial cancers growth and immune suppression. RESULTS: MM-BMSC inhibited proliferation of T cells (P = 0.0138), promoted senescence of T cells (P < 0...
April 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28514765/bmx-etk-promotes-cell-proliferation-and-tumorigenicity-of-cervical-cancer-cells-through-pi3k-akt-mtor-and-stat3-pathways
#11
Yuanyuan Li, Nan Cui, Peng-Sheng Zheng, Wen-Ting Yang
Bone marrow X-linked kinase (BMX, also known as Etk) has been reported to be involved in cell proliferation, differentiation, apoptosis, migration and invasion in several types of tumors, but its role in cervical carcinoma remains poorly understood. In this study, we showed that BMX expression exhibits a gradually increasing trend from normal cervical tissue to cervical cancer in situ and then to invasive cervical cancer tissue. Through BMX-IN-1, a potent and irreversible BMX kinase inhibitor, inhibited the expression of BMX, the cell proliferation was significantly decreased...
April 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28514724/sirna-mediated-inactivation-of-her3-improves-the-antitumour-activity-and-sensitivity-of-gefitinib-in-gastric-cancer-cells
#12
Heng-Heng Yuan, Ying-Nan Yang, Jian-Hua Zhou, Yan-Jing Li, Li-Ying Wang, Jun-Wei Qin, Tao Liu, Zhen-Zhen Li, Qing-Xin Zhou, Xiao-Li Wei, Ting-Ting Zhang, Peng Huang, Wen-Jie Zhang, Lei Liu, Xiao-Xue Du, Yu Han
The human EGFR family consists of four type-1 transmembrane tyrosine kinase receptors: HER1 (EGFR, ErbB1), HER2 (Neu, ErbB2), HER3 (ErbB3), and HER4 (ErbB4). HER3 can dimerize with EGFR, HER2 and even c-Met and likely plays a central role in the response to EGFR-targeted therapy. Because HER3 lacks significant kinase activity and cannot be inhibited by tyrosine kinase inhibitors, neutralizing antibodies and alternative inhibitors of HER3 have been sought as cancer therapeutics. Here, we describe the stable suppression of HER3 mRNA and protein using siRNA...
April 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28513879/the-therapeutic-potential-of-pi3k-akt-mtor-inhibitors-in-breast-cancer-rational-and-progress
#13
Afsane Bahrami, Majid Khazaei, Soodabeh Shahidsales, Seyed Mahdi Hassanian, Malihe Hasanzadeh, Mina Maftouh, Gordon A Ferns, Amir Avan
Breast cancer is the most commonly diagnosed cancer in women. The PI3K/AKT/ mTOR pathway is among the most frequently dysregulated pathways in patients with breast cancer. The activation of this pathway is associated with increased cell growth and clinical outcome, and its overexpression is associated with a poor prognosis. It has been proposed that it may be of importance as a potential therapeutic target in the treatment of breast cancer. The aim of current review is to provide an overview of the potential utility of PI3K/Akt/mTOR inhibitors in patients with breast cancer, with particular emphasis on recent preclinical and clinical studies...
May 17, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28513565/epidermal-growth-factor-receptor-cell-proliferation-signaling-pathways
#14
REVIEW
Ping Wee, Zhixiang Wang
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation...
May 17, 2017: Cancers
https://www.readbyqxmd.com/read/28509866/hdac8-prevents-anthrax-lethal-toxin-induced-cell-cycle-arrest-through-silencing-pten-in-human-monocytic-thp-1-cells
#15
Soon-Duck Ha, Woohyun Cho, Sung Ouk Kim
Anthrax lethal toxin (LeTx) is a cytotoxic virulence factor that causes cell cycle arrest and cell death in various cell types. However, susceptibility to the cytotoxic effects varies depending on cell types. In proliferating monocytes, LeTx has only transient cytotoxic effects due to activation of the phosphoinositide 3-kinase (PI3K)-AKT-mediated adaptive responses. To date, the mechanism of LeTx in activating PI3K-AKT signaling axis is unknown. This study shows that the histone deacetylase 8 (HDAC8) is involved in activating PI3K-AKT signaling axis through down-regulating the phosphatase and tensin homolog 1 (PTEN) in human monocytic THP-1 cells...
May 16, 2017: Toxins
https://www.readbyqxmd.com/read/28507556/differential-effects-of-phosphatidylinositol-4-kinase-pi4k-and-3-kinase-pi3k-inhibitors-on-stomatal-responses-to-environmental-signals
#16
Sho Takahashi, Keina Monda, Takumi Higaki, Mimi Hashimoto-Sugimoto, Juntaro Negi, Seiichiro Hasezawa, Koh Iba
Specific cellular components including products of phosphatidylinositol (PI) metabolism play an important role as signaling molecules in stomatal responses to environmental signals. In this study, pharmacological inhibitors of a set of cellular components, including PI4-kinase (PI4K) and PI3K, were used to investigate stomatal closure in response to CO2, darkness, and abscisic acid (ABA). Treatment with PAO, a specific inhibitor of PI4K, specifically inhibited the stomatal response to CO2 compared with that to darkness and ABA...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28506751/recent-progress-towards-clinically-relevant-atp-competitive-akt-inhibitors
#17
REVIEW
Bayard R Huck, Igor Mochalkin
The frequency of PI3K/Akt/mTOR (PAM) Pathway mutations in human cancers sparked interest to determine if the pathway is druggable. The modest clinical benefit observed with mTOR rapalogs (temsirolimus and everolimus) provided further motivation to identify additional nodes of pathway inhibition that lead to improved clinical benefit. Akt is a central signaling node of the PAM pathway and could be an ideal target for improved pathway inhibition. Furthermore, inhibitors of Akt may be especially beneficial in tumors with Akt1 mutations...
April 29, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28505619/bone-marrow-mesenchymal-stem-cell-transplantation-increases-gap-43-expression-via-erk1-2-and-pi3k-akt-pathways-in-intracerebral-hemorrhage
#18
Jianzhong Cui, Changmeng Cui, Ying Cui, Ran Li, Huaxin Sheng, Xiaohua Jiang, Yanxia Tian, Kaijie Wang, Junling Gao
BACKGROUND/AIMS: Intracerebral hemorrhage (ICH) occurs in hypertensive patients and results in high rates of mortality and disability. This study determined whether bone marrow mesenchymal stem cell (BMSC) transplantation affects axonal regeneration and examined the underlying mechanisms after the administration of PD98059 (p-ERK1/2 inhibitor) or/ and LY294002 (PI3K inhibitor). The hypothesis that was intended to be tested was that BMSC transplantation regulates the expression of growth-associated protein-43 (GAP-43) via the ERK1/2 and PI3K/Akt signaling pathways...
May 12, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28505221/combining-pi3k-and-parp-inhibitors-for-breast-and-ovarian-cancer-tratement
#19
R Condorelli, F André
No abstract text is available yet for this article.
May 15, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28505181/overexpression-of-pyruvate-dehydrogenase-kinase-1-in-retinoblastoma-a-potential-therapeutic-opportunity-for-targeting-vitreous-seeds-and-hypoxic-regions
#20
Swatishree Sradhanjali, Devjyoti Tripathy, Suryasnata Rath, Ruchi Mittal, Mamatha M Reddy
Pyruvate dehydrogenase kinase 1 (PDK1), a key enzyme implicated in metabolic reprogramming of tumors, is induced in several tumors including glioblastoma, breast cancer and melanoma. However, the role played by PDK1 is not studied in retinoblastoma (RB). In this study, we have evaluated the expression of PDK1 in RB clinical samples, and studied its inhibition as a strategy to decrease cell growth and migration. We show that PDK1 is specifically overexpressed in RB patient samples especially in vitreous seeds and hypoxic regions and cell lines compared to control retina using immunohistochemistry and real-time PCR...
2017: PloS One
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