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https://www.readbyqxmd.com/read/28448802/ddk-promotes-tumor-chemoresistance-and-survival-via-multiple-pathways
#1
Nanda Kumar Sasi, Arjun Bhutkar, Nathan J Lanning, Jeffrey P MacKeigan, Michael Weinreich
DBF4-dependent kinase (DDK) is a two-subunit kinase required for initiating DNA replication at individual origins and is composed of CDC7 kinase and its regulatory subunit DBF4. Both subunits are highly expressed in many diverse tumor cell lines and primary tumors, and this is correlated with poor prognosis. Inhibiting DDK causes apoptosis of tumor cells, but not normal cells, through a largely unknown mechanism. Firstly, to understand why DDK is often overexpressed in tumors, we identified gene expression signatures that correlate with DDK high- and DDK low-expressing lung adenocarcinomas...
April 24, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28429752/lncrna-hit-promotes-cell-proliferation-of-non-small-cell-lung-cancer-by-association-with-e2f1
#2
L Yu, F Fang, S Lu, X Li, Y Yang, Z Wang
Lung cancer is the leading cause of cancer-related death around the world. Long noncoding RNA (lncRNA) has pivotal roles in cancer occurrence and development. However, only a few lncRNAs have been functionally characterized. In the present study, we investigated the effects of lncRNA-HIT (HOXA transcript induced by TGFβ) expression on non-small cell lung cancer (NSCLC) cell phenotype with the gain-of-function and loss-of-function assays. We found that ectopic expression or knockdown of lncRNA-HIT markedly increased or decreased NSCLC cell proliferation, respectively...
April 21, 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/28427443/benserazide-a-dopadecarboxylase-inhibitor-suppresses-tumor-growth-by-targeting-hexokinase-2
#3
Wei Li, Mengzhu Zheng, Shuangping Wu, Suyu Gao, Mei Yang, Zhimei Li, Qiuxia Min, Weiguang Sun, Lixia Chen, Guangya Xiang, Hua Li
BACKGROUND: Hexokinase (HK) is the rate-limiting enzyme in the first reaction of glycolysis. And Hexokinase 2 (HK2) is most closely related to malignant tumor which expresses at higher level compared with normal cells. HK2 plays a pivotal role in tumor initiation and maintenance, which provides a new target for cancer therapy. METHODS: Structure-based virtual ligand screening was used in hit identification from ZINC Drug Database. Microscale thermophoresis assay was performed to evaluate the binding affinity...
April 20, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28426320/transient-exposure-to-androgens-induces-a-remarkable-self-sustained-quiescent-state-in-dispersed-prostate-cancer-cells
#4
Anh Thu Bui, Meng-Er Huang, Maryline Havard, Fanny Laurent-Tchenio, François Dautry, Thierry Tchenio
Cellular quiescence is a reversible cell growth arrest that is often assumed to require a persistence of non-permissive external growth conditions for its maintenance. In this work, we showed that androgen could induce a quiescent state that is self-sustained in a cell-autonomous manner through a "hit and run" mechanism in androgen receptor-expressing prostate cancer cells. This phenomenon required the set-up of a sustained redox imbalance and TGFβ/BMP signaling that were dependent on culturing cells at low density...
April 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28415818/mechanistic-characterization-of-a-copper-containing-thiosemicarbazone-with-potent-antitumor-activity
#5
Henning Karlsson, Mårten Fryknäs, Sara Strese, Joachim Gullbo, Gunnar Westman, Ulf Bremberg, Tobias Sjöblom, Tatjana Pandzic, Rolf Larsson, Peter Nygren
BACKGROUND: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties. MATERIALS AND METHODS: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50...
March 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414307/metabolic-inhibitors-accentuate-the-anti-tumoral-effect-of-hdac5-inhibition
#6
E Hendrick, P Peixoto, A Blomme, C Polese, N Matheus, J Cimino, A Frère, A Mouithys-Mickalad, D Serteyn, L Bettendorff, B Elmoualij, P De Tullio, G Eppe, F Dequiedt, V Castronovo, D Mottet
The US FDA approval of broad-spectrum histone deacetylase (HDAC) inhibitors has firmly laid the cancer community to explore HDAC inhibition as a therapeutic approach for cancer treatment. Hitting one HDAC member could yield clinical benefit but this required a complete understanding of the functions of the different HDAC members. Here we explored the consequences of specific HDAC5 inhibition in cancer cells. We demonstrated that HDAC5 inhibition induces an iron-dependent reactive oxygen species (ROS) production, ultimately leading to apoptotic cell death as well as mechanisms of mitochondria quality control (mitophagy and mitobiogenesis)...
April 17, 2017: Oncogene
https://www.readbyqxmd.com/read/28413197/structure-and-function-of-helicobacter-pylori-caga-the-first-identified-bacterial-protein-involved-in-human-cancer
#7
REVIEW
Masanori Hatakeyama
Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor of gastric cancer. The cagA gene-encoded CagA protein is delivered into gastric epithelial cells via bacterial type IV secretion, where it undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs. Delivered CagA then acts as a non-physiological scaffold/hub protein by interacting with multiple host signaling molecules, most notably the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1/MARK, in both tyrosine phosphorylation-dependent and -independent manners...
2017: Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
https://www.readbyqxmd.com/read/28410781/virtual-screen-to-nmr-vs2nmr-discovery-of-fragment-hits-for-the-cbp-bromodomain
#8
Dimitrios Spiliotopoulos, Jian Zhu, Eike-Christian Wamhoff, Nicholas Deerain, Jean-Rémy Marchand, Jonas Aretz, Christoph Rademacher, Amedeo Caflisch
Overexpression of the CREB-binding protein (CBP), a bromodomain-containing transcription coactivator involved in a variety of cellular processes, has been observed in several types of cancer with a correlation to aggressiveness. We have screened a library of nearly 1500 fragments by high-throughput docking into the CBP bromodomain followed by binding energy evaluation using a force field with electrostatic solvation. Twenty of the 39 fragments selected by virtual screening are positive in one or more ligand-observed nuclear magnetic resonance (NMR) experiments...
April 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28410492/synthesis-and-biological-evaluation-of-novel-indole-pyrimidine-hybrids-bearing-morpholine-and-thiomorpholine-moieties
#9
Peng-Cheng Diao, Qiu Li, Meng-Jin Hu, Yu-Feng Ma, Wen-Wei You, Kwon Ho Hong, Pei-Liang Zhao
Based on our previous screening hit compound 1, a series of novel indole-pyrimidine hybrids possessing morpholine or thiomorpholine moiety were synthesized via an efficient one-pot multistep synthetic method. The antiproliferative activities of the synthesized compounds were evaluated in vitro against four cancer cell lines including HeLa, MDA-MB-231, MCF-7, and HCT116. The results revealed that most compounds possessed moderate to excellent potency. The IC50 values of the most promising compound 15 are 0...
April 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28409725/genetic-landscape-of-sporadic-vestibular-schwannoma
#10
Aril Løge Håvik, Ove Bruland, Erling Myrseth, Hrvoje Miletic, Mads Aarhus, Per-Morten Knappskog, Morten Lund-Johansen
OBJECTIVE Vestibular schwannoma (VS) is a benign tumor with associated morbidities and reduced quality of life. Except for mutations in NF2, the genetic landscape of VS remains to be elucidated. Little is known about the effect of Gamma Knife radiosurgery (GKRS) on the VS genome. The aim of this study was to characterize mutations occurring in this tumor to identify new genes and signaling pathways important for the development of VS. In addition, the authors sought to evaluate whether GKRS resulted in an increase in the number of mutations...
April 14, 2017: Journal of Neurosurgery
https://www.readbyqxmd.com/read/28397890/discovery-and-optimization-of-selective-inhibitors-of-protein-arginine-methyltransferase-5-by-docking-based-virtual-screening
#11
Yan Ye, Bidong Zhang, Ruifeng Mao, Chenhua Zhang, Yulan Wang, Jing Xing, Yu-Chih Liu, Xiaomin Luo, Hong Ding, Yaxi Yang, Bing Zhou, Hualiang Jiang, Kaixian Chen, Cheng Luo, Mingyue Zheng
Protein arginine methyltransferase 5 (PRMT5) is a type II PRMT enzyme critical for diverse cellular processes and different types of cancers. Many efforts have been made to discover novel scaffold PRMT5 inhibitors. Herein, we report the discovery of DC_P33 as a hit compound of PRMT5 inhibitor, identified by molecular docking based virtual screening and (3)H-labeled radioactive methylation assays. Structure-activity relationship (SAR) analysis was performed on the analogs of DC_P33 and then structural modifications were done to improve its activity...
April 11, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28396835/using-a-biologically-annotated-library-to-analyze-the-anticancer-mechanism-of-serine-palmitoyl-transferase-spt-inhibitors
#12
Osamu Sano, Ken-Ichi Kazetani, Ryutaro Adachi, Osamu Kurasawa, Tomohiro Kawamoto, Hidehisa Iwata
Mechanistic understanding is crucial to anticancer drug discovery. Here, we reveal that inhibition of serine palmitoyl transferase (SPT), the rate-limiting enzyme in sphingolipid synthesis, induced death in a lung cancer cell line via a necrosis-dependent pathway. To elucidate the mechanism of cell death induced by SPT inhibition, a biologically annotated library of diverse compounds was screened with an SPT inhibitor. This analysis identified suppressors of SPT inhibitor-mediated cell death. Further analysis using hit compounds from this screening revealed that SPT inhibitors induce COX-2 expression, leading to necrosis-dependent cell death...
April 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28396636/enhancing-drug-efficacy-and-therapeutic-index-through-cheminformatics-based-selection-of-small-molecule-binary-weapons-that-improve-transporter-mediated-targeting-a-cytotoxicity-system-based-on-gemcitabine
#13
Justine M Grixti, Steve O'Hagan, Philip J Day, Douglas B Kell
The transport of drug molecules is mainly determined by the distribution of influx and efflux transporters for which they are substrates. To enable tissue targeting, we sought to develop the idea that we might affect the transporter-mediated disposition of small-molecule drugs via the addition of a second small molecule that of itself had no inhibitory pharmacological effect but that influenced the expression of transporters for the primary drug. We refer to this as a "binary weapon" strategy. The experimental system tested the ability of a molecule that on its own had no cytotoxic effect to increase the toxicity of the nucleoside analog gemcitabine to Panc1 pancreatic cancer cells...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28396011/suppression-of-nfat5-mediated-inflammation-and-chronic-arthritis-by-novel-%C3%AE%C2%BAb-binding-inhibitors
#14
Eun-Jin Han, Hyun Young Kim, Naeun Lee, Nam-Hoon Kim, Seung-Ah Yoo, H Moo Kwon, Dae-Myung Jue, Yune-Jung Park, Chul-Soo Cho, Tran Quang De, Dae Young Jeong, Hee-Jong Lim, Woo Kyu Park, Ge Hyeong Lee, Heeyeong Cho, Wan-Uk Kim
Nuclear factor of activated T cells 5 (NFAT5) has been implicated in the pathogenesis of various human diseases, including cancer and arthritis. However, therapeutic agents inhibiting NFAT5 activity are currently unavailable. To discover NFAT5 inhibitors, a library of >40,000 chemicals was screened for the suppression of nitric oxide, a direct target regulated by NFAT5 activity, through high-throughput screening. We validated the anti-NFAT5 activity of 198 primary hit compounds using an NFAT5-dependent reporter assay and identified the novel NFAT5 suppressor KRN2, 13-(2-fluoro)-benzylberberine, and its derivative KRN5...
March 31, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28392986/prioritisation-of-structural-variant-calls-in-cancer-genomes
#15
Miika J Ahdesmäki, Brad A Chapman, Pablo Cingolani, Oliver Hofmann, Aleksandr Sidoruk, Zhongwu Lai, Gennadii Zakharov, Mikhail Rodichenko, Mikhail Alperovich, David Jenkins, T Hedley Carr, Daniel Stetson, Brian Dougherty, J Carl Barrett, Justin H Johnson
Sensitivity of short read DNA-sequencing for gene fusion detection is improving, but is hampered by the significant amount of noise composed of uninteresting or false positive hits in the data. In this paper we describe a tiered prioritisation approach to extract high impact gene fusion events from existing structural variant calls. Using cell line and patient DNA sequence data we improve the annotation and interpretation of structural variant calls to best highlight likely cancer driving fusions. We also considerably improve on the automated visualisation of the high impact structural variants to highlight the effects of the variants on the resulting transcripts...
2017: PeerJ
https://www.readbyqxmd.com/read/28389630/identification-of-small-molecule-inhibitors-of-the-aurora-a-tpx2-complex
#16
Italia Anna Asteriti, Frederick Daidone, Gianni Colotti, Serena Rinaldo, Patrizia Lavia, Giulia Guarguaglini, Alessandro Paiardini
Aurora kinases are a family of cell division regulators that govern the correct assembly of a bipolar mitotic spindle and the fidelity of chromosome segregation. Their overexpression is associated with genomic instability and aneuploidy, and is frequently observed in cancer. Accordingly, competitive inhibitors targeting Aurora kinase activity at the ATP-binding site are being investigated for therapeutic purposes. Despite promising pre-clinical data, these molecules display moderate effects in clinical trials and incomplete selectivity, either against distinct family members, or other kinases...
March 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28388536/long-noncoding-rna-ror-regulates-chemoresistance-in-docetaxel-resistant-lung-adenocarcinoma-cells-via-epithelial-mesenchymal-transition-pathway
#17
Yan Pan, Jing Chen, Leilei Tao, Kai Zhang, Rui Wang, Xiaoyuan Chu, Longbang Chen
Emerging evidence indicates that the dysregulation of long non-coding RNAs (lncRNAs) contributes to the development and progression of lung adenocarcinoma (LAD), however the underlying mechanism of action of lncRNAs remains unclear. It is well known that the effective treatment of cancers has been hindered by drug resistance in the clinical setting. Epithelial-mesenchymal transition (EMT) has been recognized to be involved in acquiring drug resistance, cell migration and invasion properties in several types of cancer...
March 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28386598/defining-rna-small-molecule-affinity-landscapes-enables-design-of-a-small-molecule-inhibitor-of-an-oncogenic-noncoding-rna
#18
Sai Pradeep Velagapudi, Yiling Luo, Tuan Tran, Hafeez S Haniff, Yoshio Nakai, Mohammad Fallahi, Gustavo J Martinez, Jessica L Childs-Disney, Matthew D Disney
RNA drug targets are pervasive in cells, but methods to design small molecules that target them are sparse. Herein, we report a general approach to score the affinity and selectivity of RNA motif-small molecule interactions identified via selection. Named High Throughput Structure-Activity Relationships Through Sequencing (HiT-StARTS), HiT-StARTS is statistical in nature and compares input nucleic acid sequences to selected library members that bind a ligand via high throughput sequencing. The approach allowed facile definition of the fitness landscape of hundreds of thousands of RNA motif-small molecule binding partners...
March 22, 2017: ACS Central Science
https://www.readbyqxmd.com/read/28385785/imatinib-and-spironolactone-suppress-hepcidin-expression
#19
Katarzyna Mleczko-Sanecka, Ana Rita da Silva, Debora Call, Joana Neves, Nikolai Schmeer, Georg Damm, Daniel Seehofer, Martina U Muckenthaler
Disorders of iron metabolism are largely attributed to an excessive or insufficient expression of hepcidin, the master regulator of systemic iron homeostasis. Here, we investigated whether drugs targeting genetic regulators of hepcidin can affect iron homeostasis. We focused our efforts on drugs approved for clinical use to enable repositioning strategies and/or to reveal iron-related side effects of widely prescribed therapeutics. To identify hepcidin-modulating therapeutics, we reevaluated data generated by a genome-wide RNAi screen for hepcidin regulators...
April 6, 2017: Haematologica
https://www.readbyqxmd.com/read/28381655/establishment-of-a-genome-wide-and-quantitative-protocol-for-assessment-of-transcriptional-activity-at-human-retrotransposon-l1-antisense-promoters
#20
Koichi Ishiguro, Saneyuki Higashino, Hideki Hirakawa, Shusei Sato, Yasunori Aizawa
Long interspersed element 1 (L1) retrotransposon sequences are widespread in the human genome, occupying ~500,000 locations. The majority of L1s have lost their retrotransposition capability, although a significant population of human L1s maintains bidirectional transcriptional activity from the internal promoter. While the sense promoter drives transcription of the entire L1 mRNA and leads to L1 retrotransposition, the antisense promoter (ASP) transcribes L1-gene chimeric RNAs that include neighboring exon sequences...
April 3, 2017: Genes & Genetic Systems
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