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https://www.readbyqxmd.com/read/28941356/computational-approaches-to-identify-genetic-interactions-for-cancer-therapeutics
#1
Graeme Benstead-Hume, Sarah K Wooller, Frances M G Pearl
The development of improved cancer therapies is frequently cited as an urgent unmet medical need. Here we describe how genetic interactions are being therapeutically exploited to identify novel targeted treatments for cancer. We discuss the current methodologies that use 'omics data to identify genetic interactions, in particular focusing on synthetic sickness lethality (SSL) and synthetic dosage lethality (SDL). We describe the experimental and computational approaches undertaken both in humans and model organisms to identify these interactions...
September 23, 2017: Journal of Integrative Bioinformatics
https://www.readbyqxmd.com/read/28939533/comparative-mapping-of-on-targets-and-off-targets-for-the-discovery-of-anti-trypanosomatid-folate-pathway-inhibitors
#2
Joanna Panecka-Hofman, Ina Pöhner, Francesca Spyrakis, Talia Zeppelin, Flavio Di Pisa, Lucia Dello Iacono, Alessio Bonucci, Antonio Quotadamo, Alberto Venturelli, Stefano Mangani, Maria Paola Costi, Rebecca C Wade
BACKGROUND: Multi-target approaches are necessary to properly analyze or modify the function of a biochemical pathway or a protein family. An example of such a problem is the repurposing of the known human anti-cancer drugs, antifolates, as selective anti-parasitic agents. This requires considering a set of experimentally validated protein targets in the folate pathway of major pathogenic trypanosomatid parasites and humans: (i) the primary parasite on-targets: pteridine reductase 1 (PTR1) (absent in humans) and bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS), (ii) the primary off-targets: human DHFR and TS, and (iii) the secondary on-target: human folate receptor β, a folate/antifolate transporter...
September 20, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28938696/the-molecular-mechanisms-of-chemoresistance-in-cancers
#3
REVIEW
Hua-Chuan Zheng
Overcoming intrinsic and acquired drug resistance is a major challenge in treating cancer patients because chemoresistance causes recurrence, cancer dissemination and death. This review summarizes numerous molecular aspects of multi-resistance, including transporter pumps, oncogenes (EGFR, PI3K/Akt, Erk and NF-κB), tumor suppressor gene (p53), mitochondrial alteration, DNA repair, autophagy, epithelial-mesenchymal transition (EMT), cancer stemness, and exosome. The chemoresistance-related proteins are localized to extracellular ligand, membrane receptor, cytosolic signal messenger, and nuclear transcription factors for various events, including proliferation, apoptosis, EMT, autophagy and exosome...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938672/comparing-the-clinical-efficacy-of-abiraterone-acetate-enzalutamide-and-orteronel-in-patients-with-metastatic-castration-resistant-prostate-cancer-by-performing-a-network-meta-analysis-of-eight-randomized-controlled-trials
#4
Minyong Kang, Chang Wook Jeong, Cheol Kwak, Ja Hyeon Ku, Hyeon Hoe Kim
Various novel androgen receptor (AR) targeting drugs have been developed recently and have shown beneficial effects on survival in patients with metastatic castration-resistant prostate cancer (mCRPC). However, no consensus has been reached regarding which of these agents provides the most favorable oncological outcomes. Here, we aimed to compare the efficacy of novel AR-targeted agents by performing a network meta-analysis of randomized controlled trials (RCTs). We included eight RCTs for men with mCRPC treated with one of the AR targeting agents: abiraterone acetate, enzalutamide, or orteronel...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938651/positive-transcription-elongation-factor-b-p-tefb-is-a-therapeutic-target-in-human-multiple-myeloma
#5
Yu Zhang, Liang Zhou, Yun Leng, Yun Dai, Robert Z Orlowski, Steven Grant
The role of the positive RNA Pol II regulator, P-TEFb (positive transcription elongation factor b), in maintenance of the anti-apoptotic protein Mcl-1 and bortezomib (btz) resistance was investigated in human multiple myeloma (MM) cells. Mcl-1 was up-regulated in all MM lines tested, including bortezomib-resistant lines, human MM xenograft mouse models, and primary CD138(+) MM cells. Mcl-1 over-expression significantly reduced bortezomib lethality, indicating a functional role for Mcl-1 in bortezomib resistance...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938644/intravascular-ultrasound-guidance-in-drug-eluting-stents-implantation-a-meta-analysis-and-trial-sequential-analysis-of-randomized-controlled-trials
#6
Cheng Qian, Hong Feng, Jianlei Cao, Guangyu Zhang, Yanggan Wang
OBJECTIVE: Previous evidence suggested that intravascular ultrasound (IVUS) guidance could improve outcomes after drug-eluting stents (DES) placement, largely driven by data from observational studies. We, therefore, performed a meta-analysis and trial sequential analysis of randomized controlled trials to overcome this limitation. RESULTS: The retrieval process yielded 7 RCTs with 3,192 patients. Compared to the angiography guidance, IVUS-guided DES implantation was associated with a significant reduction in the major adverse cardiac events (MACE) (OR 0...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938641/potential-independent-action-of-sigma-receptor-ligands-through-inhibition-of-the-kv2-1-channel
#7
Xinying Liu, Yingmei Fu, Huan Yang, Timur Mavlyutov, Jun Li, Christopher R McCurdy, Lian-Wang Guo, Bikash R Pattnaik
The sigma-1 receptor (σ1-R) and sigma-2 receptor (σ2-R) are potential drug targets for treatment of cancer, pain, depression, retinal degeneration and other neuronal diseases. Previous reports show that sigma-1 receptor modulates the activities of multiple channels. We are interested in possible sigma receptor modulation of Kv2.1, a K(+) channel abundant in retinal photoreceptors. We tested the effect of established sigma receptor ligands on Kv2.1 channels which were stably expressed in HEK293 cells. Surprisingly, σ1-R antagonists inhibited Kv2...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938624/addition-of-2-ethylamino-acetonitrile-group-to-nitroxoline-results-in-significantly-improved-anti-tumor-activity-in-vitro-and-in-vivo
#8
Ana Mitrović, Izidor Sosič, Špela Kos, Urša Lampreht Tratar, Barbara Breznik, Simona Kranjc, Bojana Mirković, Stanislav Gobec, Tamara Lah, Gregor Serša, Janko Kos
Lysosomal cysteine peptidase cathepsin B, involved in multiple processes associated with tumor progression, is validated as a target for anti-cancer therapy. Nitroxoline, a known antimicrobial agent, is a potent and selective inhibitor of cathepsin B, hence reducing tumor progression in vitro and in vivo. In order to further improve its anti-cancer properties we developed a number of derivatives using structure-based chemical synthesis. Of these, the 7-aminomethylated derivative (compound 17) exhibited significantly improved kinetic properties over nitroxoline, inhibiting cathepsin B endopeptidase activity selectively...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938620/pathological-expression-of-tissue-factor-confers-promising-antitumor-response-to-a-novel-therapeutic-antibody-sc1-in-triple-negative-breast-cancer-and-pancreatic-adenocarcinoma
#9
Xuesai Zhang, Qingrou Li, Hui Zhao, Lanping Ma, Tao Meng, Jianchang Qian, Rui Jin, Jingkang Shen, Ker Yu
The pathological presence of tissue factor (TF) in cancer cells promotes tumor-initiated thrombosis and cancer metastasis. We found that TF is aberrantly present in large percentage of aggressive triple negative breast cancer (TNBC) and pancreatic adenocarcinoma (PaC), two most lethal forms of malignancy that urgently need effective treatment. TF expression in TNBC clustered with higher levels of vimentin, basal-type keratins KRT5/14 and caveolin-1 but lower levels of luminal-type biomarkers. We developed a novel and specific anti-TF therapeutic antibody SC1, which displayed an exceedingly high potency against TF extracellular domain (EC50: 0...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938619/anti-cancer-efficacy-of-biotinylated-chitosan-nanoparticles-in-liver-cancer
#10
Mingrong Cheng, Weiping Zhu, Qing Li, Dejian Dai, Yiming Hou
The present study investigated the synthesis of biotinylated chitosan (Bio-CS) from chitosan using a nanomaterial skeleton with biotin and the successful targeting of the formulation in liver cancer cells. Bio-CS was validated by fourier transformed infrared spectroscopy and hydrogen(-1) nuclear magnetic resonance spectroscopy. Bio-CS and plasmid DNA were used to construct Bio-CS/plasmid DNA nanoparticles according to the optimal molar ratio of 1:1 and the optimal pH-value of 5.5. Under these conditions, the parameters mean particle size, potential, encapsulation rate and drug loading, were 82...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938616/identification-of-potential-cancer-related-pseudogenes-in-lung-adenocarcinoma-based-on-cerna-hypothesis
#11
Yunzhen Wei, Zhiqiang Chang, Cheng Wu, Yinling Zhu, Kun Li, Yan Xu
Pseudogenes are initially regarded as non-functional genomic fossils resulted from inactivating gene mutations during evolution. Far from being silent, pseudogenes are proved to regulate the expression of protein-coding genes through function as microRNA sponge in vivo. The aim of our study was to propose an integrative systems biology approach to identify disease pseudogenes base on competitive endogenous RNA (ceRNA) hypothesis. Here, we applied our method to lung adenocarcinoma (LUAD) RNASeq data from TCGA and identified 33 candidate pseudogenes...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938614/phenformin-enhances-the-therapeutic-effect-of-selumetinib-in-kras-mutant-non-small-cell-lung-cancer-irrespective-of-lkb1-status
#12
Jun Zhang, Sreenivas Nannapaneni, Dongsheng Wang, Fakeng Liu, Xu Wang, Rui Jin, Xiuju Liu, Mohammad Aminur Rahman, Xianghong Peng, Guoqing Qian, Zhuo G Chen, Kwok-Kin Wong, Fadlo R Khuri, Wei Zhou, Dong M Shin
MEK inhibition is potentially valuable in targeting KRAS-mutant non-small cell lung cancer (NSCLC). Here, we analyzed whether concomitant LKB1 mutation alters sensitivity to the MEK inhibitor selumetinib, and whether the metabolism drug phenformin can enhance the therapeutic effect of selumetinib in isogenic cell lines with different LKB1 status. Isogenic pairs of KRAS-mutant NSCLC cell lines A549, H460 and H157, each with wild-type and null LKB1, as well as genetically engineered mouse-derived cell lines 634 (kras(G12D/wt)/p53(-/-)/lkb1(wt/wt)) and t2 (kras(G12D/wt)/p53(-/-)/lkb1(-/-)) were used in vitro to analyze the activities of selumetinib, phenformin and their combination...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938602/activation-of-cancerous-inhibitor-of-pp2a-cip2a-contributes-to-lapatinib-resistance-through-induction-of-cip2a-akt-feedback-loop-in-erbb2-positive-breast-cancer-cells
#13
Ming Zhao, Erin W Howard, Amanda B Parris, Zhiying Guo, Qingxia Zhao, Zhikun Ma, Ying Xing, Bolin Liu, Susan M Edgerton, Ann D Thor, Xiaohe Yang
Lapatinib, a small molecule ErbB2/EGFR inhibitor, is FDA-approved for the treatment of metastatic ErbB2-overexpressing breast cancer; however, lapatinib resistance is an emerging clinical challenge. Understanding the molecular mechanisms of lapatinib-mediated anti-cancer activities and identifying relevant resistance factors are of pivotal significance. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that is overexpressed in breast cancer. Our study investigated the role of CIP2A in the anti-cancer efficacy of lapatinib in ErbB2-overexpressing breast cancer cells...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938600/application-of-dual-targeting-drug-delivery-system-for-the-improvement-of-anti-glioma-efficacy-of-doxorubicin
#14
Zhenliang Sun, Xuebing Yan, YiBo Liu, Linsheng Huang, Cheng Kong, Xiao Qu, Man Wang, Renyuan Gao, Huanlong Qin
Chemotherapy of glioma is always hampered by the unsatisfactory tumor accumulation of drugs, of which the most noticeable obstacle is the limited drug permeability from vessels into tumor inner. In the present study, we developed a novel nanocarrier for the delivery of doxorubicin to brain tumor. Such novel drug delivery system was mainly composed of a tumor homing peptide and DOX-loaded PLA nanoparticles (AP1-NP-DOX). CRKRLDRNC peptide, named as AP1, was a newly glioma affinity peptide which could specifically binds to interleukin-4 receptor (IL-4R), highly expressing on both glioma cells and angiogenesis...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938590/ocular-toxicities-associated-with-targeted-anticancer-agents-an-analysis-of-clinical-data-with-management-suggestions
#15
Chen Fu, Dan S Gombos, Jared Lee, Goldy C George, Kenneth Hess, Andrew Whyte, David S Hong
Ocular toxicities are among the most common adverse events resulting from targeted anticancer agents and are becoming increasingly relevant in the management of patients on these agents. The purpose of this study is to provide a framework for management of these challenging toxicities based on objective data from FDA labels and from analysis of the literature. All oncologic drugs approved by the FDA up to March 14, 2015, were screened for inclusion. A total of 16 drugs (12 small-molecule drugs and 4 monoclonal antibodies) were analyzed for ocular toxicity profiles based on evidence of ocular toxicity...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938577/mitochondria-chaperone-grp75-moonlighting-as-a-cell-cycle-controller-to-derail-endocytosis-provides-an-opportunity-for-nanomicrosphere-intracellular-delivery
#16
Zhihui Gao, Xiuran Niu, Qing Zhang, Hang Chen, Aiai Gao, Shanshan Qi, Rong Xiang, Mattias Belting, Sihe Zhang
Understanding how cancer cells regulate endocytosis during the cell cycle could lead us to capitalize this event pharmacologically. Although certain endocytosis pathways are attenuated during mitosis, the endocytosis shift and regulation during the cell cycle have not been well clarified. The conventional concept of glucose-regulated proteins (GRPs) as protein folding chaperones was updated by discoveries that translocated GRPs assume moonlighting functions that modify the immune response, regulate viral release, and control intracellular trafficking...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938567/gemcitabine-induced-heparanase-promotes-aggressiveness-of-pancreatic-cancer-cells-via-activating-egfr-signaling
#17
Jin-Wen Song, Ying-Xia Tan, Su-Bo Li, Shi-Kun Zhang, Lu-Ming Wan, Shou-Ping Ji, Hong Zhou, Zhi-Hang Zhou, Feng Gong
Pancreatic cancer (PC), characterized by aggressive local invasion and metastasis, is one of the most malignant cancers. Gemcitabine is currently used as the standard drug for the treatment of advanced and metastatic PC, but with limited efficacy. In this study, we demonstrated that gemcitabine increased the expression of heparanase (HPA1), the only known mammalian endoglycosidase capable of cleaving heparan sulfate, both in vitro and in vivo. Furthermore, overexpression of HPA1 in PC cell lines enhanced proliferation and invasion, accompanied with elevated phosphorylation of EGFR...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938559/doxorubicin-loaded-platelets-conjugated-with-anti-cd22-mabs-a-novel-targeted-delivery-system-for-lymphoma-treatment-with-cardiopulmonary-avoidance
#18
Peipei Xu, Huaqin Zuo, Rongfu Zhou, Fan Wang, Xu Liu, Jian Ouyang, Bing Chen
B-cell lymphoma accounts for approximately 85% of all adult non-Hodgkin's lymphoma cases. Doxorubicin (DOX) is an indispensable drug for the treatment of non-Hodgkin's lymphoma. However, DOX causes severe cardiotoxicity, which limits its use in conventional treatment strategies. In this study, we developed a novel drug delivery system for lymphoma treatment: DOX-loaded platelets that were conjugated with anti-CD22 monoclonal antibodies (mAbs) (DOX-platelet-CD22). Platelets are bio- and immune-compatible drug carriers that can prolong the circulation time of drugs...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938558/human-menstrual-blood-derived-mesenchymal-stem-cells-as-a-cellular-vehicle-for-malignant-glioma-gene-therapy
#19
Xiao-Jun Wang, Bing-Yu Xiang, Ya-Hui Ding, Lu Chen, Hai Zou, Xiao-Zhou Mou, Charlie Xiang
Despite many advances in conventional treatment strategies, there is no effective treatment modality for malignant gliomas. Gene therapy may offer a promising option for gliomas and several gene therapy approaches have shown anti-tumor efficiency in previous studies. Mesenchymal stem cell-based gene therapies, in which stem cells are genetically engineered to express therapeutic molecules, have shown tremendous potential because of their innate homing ability. In this study, human menstrual blood-derived MSCs (MenSC), a novel type of multipotential MSCs displays tropism for human malignant glioma when used as a gene delivery vehicle for therapeutics...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938534/targeting-of-the-mapk-and-akt-pathways-in-conjunctival-melanoma-shows-potential-synergy
#20
Jinfeng Cao, Renier C Heijkants, Aart G Jochemsen, Mehmet Dogrusöz, Mark J de Lange, Pieter A van der Velden, Sjoerd H van der Burg, Martine J Jager, Robert M Verdijk
PURPOSE: Conjunctival melanoma (CM) is a rare but lethal form of cancer. Similar to cutaneous melanoma, CM frequently carries activating mutations in BRAF and NRAS. We studied whether CM as well as conjunctival benign and premalignant melanocytic lesions express targets in the mitogen-activated protein kinase (MAPK) and AKT pathways, and whether specific inhibitors can suppress CM growth in vitro. METHODS: 131 conjunctival lesions obtained from 129 patients were collected...
August 29, 2017: Oncotarget
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