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https://www.readbyqxmd.com/read/28938696/the-molecular-mechanisms-of-chemoresistance-in-cancers
#1
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/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
#2
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/28938577/mitochondria-chaperone-grp75-moonlighting-as-a-cell-cycle-controller-to-derail-endocytosis-provides-an-opportunity-for-nanomicrosphere-intracellular-delivery
#3
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/28938160/nilotinib-enhances-tumor-angiogenesis-and-counteracts-vegfr2-blockade-in-an-orthotopic-breast-cancer-xenograft-model-with-desmoplastic-response
#4
Sara Zafarnia, Jessica Bzyl-Ibach, Igor Spivak, Yongping Li, Susanne Koletnik, Dennis Doleschel, Anne Rix, Sibylle Pochon, Isabelle Tardy, Seena Koyadan, Marc van Zandvoort, Moritz Palmowski, Fabian Kiessling, Wiltrud Lederle
Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted therapies predominantly affect nascent, immature tumor vessels. Since platelet-derived growth factor receptor (PDGFR) blockade inhibits vessel maturation and thus increases the amount of immature tumor vessels, we evaluated whether the combined PDGFR inhibition by nilotinib and VEGFR2 blockade by DC101 has synergistic therapy effects in a desmoplastic breast cancer xenograft model. In this context, besides immunohistological evaluation, molecular ultrasound imaging with BR55, the clinically used VEGFR2-targeted microbubbles, was applied to monitor VEGFR2-positive vessels noninvasively and to assess the therapy effects on tumor angiogenesis...
September 19, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28938090/small-molecule-targets-in-immuno-oncology
#5
REVIEW
Dashyant Dhanak, James P Edwards, Ancho Nguyen, Peter J Tummino
Advances in understanding the role and molecular mechanisms underlying immune surveillance and control of (pre)malignancies is revolutionizing clinical practice in the treatment of cancer. Presently, multiple biologic drugs targeting the immune checkpoint proteins PD(L)1 or CTLA4 have been approved and/or are in advanced stages of clinical development for many cancers. In addition, combination therapy with these agents and other immunomodulators is being intensively explored with the aim of improving primary response rates or prolonging overall survival...
September 21, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28937657/synthesis-of-2-4-diaminopyrimidine-core-based-derivatives-and-biological-evaluation-of-their-anti-tubercular-activities
#6
Yifan Ouyang, Hao Yang, Peng Zhang, Yu Wang, Sargit Kaur, Xuanli Zhu, Zhe Wang, Yutong Sun, Wei Hong, Yun Fong Ngeow, Hao Wang
Tuberculosis (TB) is a chronic, potentially fatal disease caused by Mycobacterium tuberculosis (Mtb). The dihyrofolate reductase in Mtb (mt-DHFR) is believed to be an important drug target in anti-TB drug development. This enzyme contains a glycerol (GOL) binding site, which is assumed to be a useful site to improve the selectivity towards human dihyrofolate reductase (h-DHFR). There have been previous attempts to design drugs targeting the GOL binding site, but the designed compounds contain a hydrophilic group, which may prevent the compounds from crossing the cell wall of Mtb to function at the whole cell level...
September 22, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28937621/the-development-of-a-melt-extruded-shellac-carrier-for-the-targeted-delivery-of-probiotics-to-the-colon
#7
Noel M Gately, James E Kennedy
Hot melt extrusion (HME) is considered an efficient technique in developing solid molecular dispersions, and has been demonstrated to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. However, most commercial enteric or pH-responsive polymers are relatively difficult to process or have high Glass Transition Temperature (Tg) values, making their use with temperature-sensitive drugs, probiotics or biologics not viable. Shellac is a natural thermoplastic, and after a review of current literature on the pharmaceutical HME process, a possible gap in the knowledge of the use of shellac to produce dosage forms by means of HME was identified...
September 22, 2017: Pharmaceutics
https://www.readbyqxmd.com/read/28936716/induction-of-reactive-oxygen-species-an-emerging-approach-for-cancer-therapy
#8
REVIEW
Zhengzhi Zou, Haocai Chang, Haolong Li, Songmao Wang
Reactive oxygen species (ROS), a group of ions and molecules, include hydroxyl radicals (·OH), alkoxyl radicals, superoxide anion (O2·-), singlet oxygen ((1)O2) and hydrogen peroxide (H2O2). Hydroxyl radicals and alkoxyl radicals are extremely and highly reactive species respectively. Endogenous ROS are mainly formed in mitochondrial respiratory chain. Low levels of ROS play important roles in regulating biological functions in mammalian cells. However, excess production of ROS can induce cell death by oxidative damaging effects to intracellular biomacromolecules...
September 21, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28936405/chemotherapy-for-hepatocellular-carcinoma-current-evidence-and-future-perspectives
#9
REVIEW
Emanuele Rinninella, Lucia Cerrito, Irene Spinelli, Marco Cintoni, Maria Cristina Mele, Maurizio Pompili, Antonio Gasbarrini
Hepatocarcinogenesis is a multistep process, heralded by abnormalities in cell differentiation and proliferation and sustained by an aberrant neoangiogenesis. Understanding the underlying molecular pathogenesis leading to hepatocellular carcinoma is a prerequisite to develop new drugs that will hamper or block the steps of these pathways. As hepatocellular carcinoma has higher arterial vascularization than normal liver, this could be a good target for novel molecular therapies. Introduction of the antiangiogenic drug sorafenib into clinical practice since 2008 has led to new perspectives in the management of this tumor...
September 28, 2017: Journal of Clinical and Translational Hepatology
https://www.readbyqxmd.com/read/28935769/mof-derived-cobalt-nanoparticles-catalyze-a-general-synthesis-of-amines
#10
Rajenahally V Jagadeesh, Kathiravan Murugesan, Ahmad S Alshammari, Helfried Neumann, Marga-Martina Pohl, Jörg Radnik, Matthias Beller
The development of base metal catalysts for the synthesis of pharmaceutically relevant compounds remains an important goal of chemical research. Here, we report that cobalt nanoparticles encapsulated by a graphitic shell are broadly effective reductive amination catalysts. Their convenient and practical preparation entailed template assembly of cobalt-diamine-dicarboxylic acid metal organic frameworks on carbon and subsequent pyrolysis under inert atmosphere. The resulting stable and reusable catalysts were active for synthesis of primary, secondary, tertiary and N-methylamines (>140 examples)...
September 21, 2017: Science
https://www.readbyqxmd.com/read/28935537/affibody-molecules-for-the-molecular-imaging-and-targeted-drug-delivery-in-the-management-of-breast-cancer
#11
REVIEW
Anindita De, Gowthamarajan Kuppusamy, Veera Venkata Satyanarayana Reddy Karri
Breast cancer is one of the leading reasons for the morbidity and mortality of cancer related death globally. The modern therapies are basically the combination of the breast-preserving surgeries or ablation with or without node biopsy or destroying the carcinoma cells adjuvant with chemotherapy, radiotherapy, hormonal or biological therapies depending upon the nature of the receptor of the cancerous cells, nature of the lymph node, as well as the tendency of the recurrence. For decade's carcinoma management suffered by the limitation of imagining, targeting and penetrability problem associated with management and cure of this deadly disease leads to unwanted chemo-toxicity and side effects...
September 18, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28935265/quinazolinone-based-rhodanine-3-acetic-acids-as-potent-aldose-reductase-inhibitors-synthesis-functional-evaluation-and-molecular-modeling-study
#12
Sherihan El-Sayed, Kamel Metwally, Abdalla A El-Shanawani, Lobna M Abdel-Aziz, Ahmed A El-Rashedy, Mahmoud E S Soliman, Luca Quattrini, Vito Coviello, Concettina la Motta
A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme...
August 24, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28935216/allosteric-modulators-targeting-cns-muscarinic-receptors
#13
REVIEW
Andreas Bock, Ramona Schrage, Klaus Mohr
Muscarinic acetylcholine receptors are G protein-coupled receptors (GPCRs) which are broadly expressed in the central nervous system (CNS) and other tissues in the periphery. They emerge as important drug targets for a number of diseases including Alzheimer's disease, Parkinson's disease, and schizophrenia. Muscarinic receptors are divided into five subtypes (M1-M5) of which M1-M4 have been crystalized. All subtypes possess at least one allosteric binding site which is located in the extracellular region of the receptor on top of the ACh (i...
September 18, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28935177/downregulation-of-foxp3-inhibits-cell-proliferation-and-enhances-chemosensitivity-to-cisplatin-in-human-lung-adenocarcinoma
#14
Chun Li, Liwei Sun, Rui Jiang, Peng Wang, Haogang Xue, Yudong Zhan, Xiaodong Gai
Our study aimed to investigate the biological role of FOXP3 expression in human lung adenocarcinoma (LAD) tissues and evaluate its involvement in cell proliferation and chemosensitivity to cisplatin in LAD cells. Paraffin-embedded tissues from 50 LAD patients were collected to detect FOXP3 and Ki-67 expression using immunohistochemistry (IHC). Downregulation of FOXP3 in A549 cells was performed using siRNA transfection. Real-time PCR or western blot assay was performed to analyze FOXP3 expression in A549 cells...
September 8, 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/28934207/evaluation-of-the-pharmacokinetic-pharmacodynamic-relationship-of-praziquantel-in-the-schistosoma-mansoni-mouse-model
#15
Nada Abla, Jennifer Keiser, Mireille Vargas, Natalie Reimers, Helmut Haas, Thomas Spangenberg
After more than 40 years of use, Praziquantel (PZQ) still remains the drug of choice for the treatment of intestinal and urogenital schistosomiasis. Its anti-parasitic activity resides primarily in the (R)-enantiomer. Hitherto neither the molecular target nor the pharmacokinetic-pharmacodynamic relationship have been fully elucidated. Here we investigated the efficacy and pharmacokinetics of PZQ in the Schistosoma mansoni mouse model to determine the key factors that drive its efficacy. Dose-response studies with racemic PZQ with or without addition of an irreversible pan-cytochrome P450 (CYP) inhibitor, 1-aminobenzotriazole (ABT), were performed...
September 21, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28934023/biomarker-enrichment-considerations-in-oncology-early-development-single-arm-studies
#16
Hong Tian, Kevin Liu
Oncology drug development has been increasingly shaped by molecularly targeted agents (MTAs), which often demonstrate differential effectiveness driven by the biomarker expression levels on tumors. Innovative statistical designs have been proposed to tackle this challenge, e.g., Freidlin et al (2005), Jiang et al (2007) and Freidlin et al (2010). All of these are essentially adaptive confirmatory Phase 3 designs that combine the testing of treatment effectiveness in the overall population with an alternative pathway for a more restrictive efficacy claim in a sensitive subpopulation...
September 21, 2017: Journal of Biopharmaceutical Statistics
https://www.readbyqxmd.com/read/28933969/psychopharmacological-advances-in-eating-disorders
#17
Hubertus Himmerich, Janet Treasure
Anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED) are the primary eating disorders (EDs). The only psychopharmacological treatment options for EDs with approval in some countries include fluoxetine for BN and lisdexamfetamine for BED. Given the high comorbidity and genetic correlations with other psychiatric disorders, it seems possible that novel medications for these conditions might also be effective in EDs. Areas Covered: The current scientific literature has increased our understanding of how medication could be beneficial for patients with EDs on a molecular, functional and behavioral level...
September 21, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28933851/design-and-structure-guided-development-of-novel-inhibitors-of-the-xeroderma-pigmentosum-group-a-xpa-protein-dna-interaction
#18
Navnath S Gavande, Pamela VanderVere-Carozza, Akaash K Mishra, Tyler L Vernon, Katherine S Pawelczak, John J Turchi
XPA is a unique and essential protein required for the nucleotide excision DNA repair pathway and represents a therapeutic target in oncology. Herein, we are the first to develop novel inhibitors of the XPA-DNA interaction through structure-guided drug design efforts. Ester derivatives of the compounds 1 (X80), 22, and 24 displayed excellent inhibitory activity (IC50 of 0.82 ± 0.18 μM and 1.3 ± 0.22 μM, respectively) but poor solubility. We have synthesized novel amide derivatives that retain potency and have much improved solubility...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28933618/novel-cns-drug-discovery-and-development-approach-model-based-integration-to-predict-neuro-pharmacokinetics-and-pharmacodynamics
#19
Elizabeth C M de Lange, Willem van den Brink, Yumi Yamamoto, Wilhelmus E A de Witte, Yin Cheong Wong
CNS drug development has been hampered by inadequate consideration of CNS pharmacokinetic (PK), pharmacodynamics (PD) and disease complexity (reductionist approach). Improvement is required via integrative model-based approaches. Areas covered: The authors summarize factors that have played a role in the high attrition rate of CNS compounds. Recent advances in CNS research and drug discovery are presented, especially with regard to assessment of relevant neuro-PK parameters. Suggestions for further improvements are also discussed...
September 21, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28933298/old-drugs-and-new-targets-as-an-outlook-for-the-treatment-of-tuberculosis
#20
Jan Zitko, Martin Doležal
Despite of the globally positive trends in epidemiology of tuberculosis, the ever increasing rates of drug-resistant strains are urging to introduce new antituberculars into clinical practice. Development of a new chemical entity from hit to marketed drug is an extremely time and resources consuming process with uncertain outcome. In this review we show that proper research of old drugs can be a very efficient way to new antituberculars. Firstly, we review the recent research on mechanism of action and molecular targets of first-line and second-line antituberculars and suggest how this knowledge can be used to design simple derivatives with improved properties...
September 20, 2017: Current Medicinal Chemistry
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