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Raquel Ciuvalschi Maia, Michelle X G Pereira, Amanda S O Hammes, Flavia C Vasconcelos, Aline R Pozzo, Thais Hancio Pereira, Ernesto R Caffarena, Cerli R Gattass
BACKGROUND: Acute myeloid leukemia (AML) represent the largest number of annual deaths from hematologic malignancy. In the United-States, it is estimated that 21.380 individuals will be diagnosed with AML and 49.5% of patients will die in 2017. Therefore, the searching for novel compounds capable of increasing the overall survival rate to the treatment of AML cells is urgent. OBJECTIVES: To investigate the cytotoxicity effect of the natural compound PA and to explore the mechanism of action of PA in AML cell lines with different phenotypes...
April 12, 2018: Anti-cancer Agents in Medicinal Chemistry
Y Zhu, Y J Shi, Y L Zhao, P Zhu
OBJECTIVE: To investigate the effects of chemotherapeutic agents widely used in clinical practice on major histocompatibility complex class I-related chain A and B (MICA/B) expression in breast cancer cells, and to explore the molecular mechanisms involved. METHODS: We examined MICA/B mRNA and surface protein expressions in breast cancer cells treated with chemotherapeutic agents by real-time RT-PCR and flow cytometry respectively. The blocking effects of ataxia telangiectasia mutated and Rad3-related kinase (ATM/ATR) inhibitor caffeine and nuclear factor κB (NF-κB) inhibitor pynolidine dithiocarbamate (PDTC) on etoposide-upregulated MICA/B mRNA and surface protein expressions were investigated...
April 18, 2018: Beijing da Xue Xue Bao. Yi Xue Ban, Journal of Peking University. Health Sciences
Arnaud Gutierrez, Jonathan M Stokes, Ivan Matic
The maintenance of DNA supercoiling is essential for the proper regulation of a plethora of biological processes. As a consequence of this mode of regulation, ahead of the replication fork, DNA replication machinery is prone to introducing supercoiled regions into the DNA double helix. Resolution of DNA supercoiling is essential to maintain DNA replication rates that are amenable to life. This resolution is handled by evolutionarily conserved enzymes known as topoisomerases. The activity of topoisomerases is essential, and therefore constitutes a prime candidate for targeting by antibiotics...
April 8, 2018: Antibiotics
Hope S Rugo, Javier Cortes, Ahmad Awada, Joyce O'Shaughnessey, Chris J Twelves, Seock-Ah Im, Alison Hannah, Lin Lu, Sherwin Sy, Katie Caygill, Deborah A Zajchowski, Darren W Davis, Mary A Tagliaferri, Ute Hoch, Edith A Perez
PURPOSE: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTCs) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP). EXPERIMENTAL DESIGN: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656/852 (77%) of patients was processed with ApoStream® to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers (Top1, Top2, Ki67, RAD51, ABCG2, ɣH2AX, TUNEL) in CTCs...
April 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Stephanie N Taylor, David H Morris, Ann K Avery, Kimberly A Workowski, Byron E Batteiger, Courtney A Tiffany, Caroline R Perry, Aparna Raychaudhuri, Nicole E Scangarella-Oman, Mohammad Hossain, Etienne F Dumont
Background: In this phase 2 study, we evaluated the efficacy and safety of oral gepotidacin, a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor, for the treatment of uncomplicated urogenital gonorrhea. Methods: Adult participants with suspected urogenital gonorrhea were enrolled and completed baseline (day 1) and test-of-cure (days 4-8) visits. Pretreatment and posttreatment urogenital swabs were collected for Neisseria gonorrhoeae (NG) culture and susceptibility testing...
April 2, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Si Chen, Qiangen Wu, Baitang Ning, Matthew Bryant, Lei Guo
Dronedarone is used to treat patients with cardiac arrhythmias and has been reported to be associated with liver injury. Our previous mechanistic work demonstrated that DNA damage-induced apoptosis contributes to the cytotoxicity of dronedarone. In this study, we examined further the underlying mechanisms and found that after a 24-h treatment of HepG2 cells, dronedarone caused cytotoxicity, G1-phase cell cycle arrest, suppression of topoisomerase II, and DNA damage in a concentration-dependent manner. We also investigated the role of cytochrome P450s (CYPs)-mediated metabolism in the dronedarone-induced toxicity using our previously established HepG2 cell lines expressing individually 14 human CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7)...
April 3, 2018: Archives of Toxicology
Magdy A H Zahran, Bishoy El-Aarag, Ahmed B M Mehany, Amany Belal, Ali S Younes
A series of novel phthalimide analogs containing an indole or brominated indole moiety were synthesized and their antimicrobial activity was evaluated. Compound 8 showed a broad spectrum activity, revealing 53-67% of erythromycin activity on the tested bacteria and 60-70% of miconazole activity on the tested fungi. Anticancer activity was evaluated on the cell lines HepG2, MCF-7, A549, H1299, and Caco2. The results revealed that the new phthalimide analog 8 has broad-spectrum anticancer activity toward all the tested cancer cell lines, followed by compound 11, which showed good activity toward all the tested cell lines except for MCF-7...
April 3, 2018: Archiv der Pharmazie
Krzysztof Ziach, Céline Chollet, Vincent Parissi, Panchami Prabhakaran, Mathieu Marchivie, Valentina Corvaglia, Partha Pratim Bose, Katta Laxmi-Reddy, Frédéric Godde, Jean-Marie Schmitter, Stéphane Chaignepain, Philippe Pourquier, Ivan Huc
Numerous essential biomolecular processes require the recognition of DNA surface features by proteins. Molecules mimicking these features could potentially act as decoys and interfere with pharmacologically or therapeutically relevant protein-DNA interactions. Although naturally occurring DNA-mimicking proteins have been described, synthetic tunable molecules that mimic the charge surface of double-stranded DNA are not known. Here, we report the design, synthesis and structural characterization of aromatic oligoamides that fold into single helical conformations and display a double helical array of negatively charged residues in positions that match the phosphate moieties in B-DNA...
April 2, 2018: Nature Chemistry
Tarani Kanta Barman, Manoj Kumar, Tarun Mathur, Eiko Namba, Diksha Singh, Tridib Chaira, Yuichi Kurosaka, Makiko Yamada, Dilip Jatashankar Upadhyay, Nobuhisa Masuda
DS-2969b is a novel GyrB inhibitor under clinical development. In this study, the in vitro activity of DS-2969b and in vivo activities of DS-2969b and its water-soluble prodrug, DS11960558, against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. DS-2969b inhibited the supercoiling activity of S. aureus DNA gyrase and the decatenation activity of its topoisomerase IV. DS-2969b showed antibacterial activity against Gram-positive aerobes but not against Gram-negative aerobes, except Moraxella catarrhalis and Haemophilus influenzae DS-2969b was active against MRSA with an MIC90 of 0...
April 2, 2018: Antimicrobial Agents and Chemotherapy
Carolina Bartolomé, María Buendía, María Benito, Pilar De la Rúa, Concepción Ornosa, Raquel Martín-Hernández, Mariano Higes, Xulio Maside
Trypanosomatids are highly prevalent pathogens of Hymenoptera; however, most molecular methods used to detect them in Apis and Bombus spp. do not allow the identification of the infecting species, which then becomes expensive and time consuming. To overcome this drawback, we developed a multiplex PCR protocol to readily identify in a single reaction the main trypanosomatids present in these hymenopterans (Lotmaria passim, Crithidia mellificae and Crithidia bombi), which will facilitate the study of their epidemiology and transmission dynamics...
March 30, 2018: Journal of Invertebrate Pathology
Mohd Afzal, Hamad A Al Lohedan, Mohammad Usman, Sartaj Tabassum
Due to the critical role of cellular enzymes necessary for cell proliferation by deciphering topological hurdles in the process of DNA replication, topoisomerases have been one of the major targets in the anticancer drug development area. A need, therefore, arises for new metallodrugs that specifically recognizes DNA and inhibits the activity of topoisomerase enzymes, herein, we report the synthesis and characterisation of new metal-based glycoconjugate entities containing heterobimetallic core CuII -SnIV (1) and NiII -SnIV (2) derived from N-glycoside ligand (L)...
March 31, 2018: Journal of Biomolecular Structure & Dynamics
Elisabeth I Heath, Filipa Lynce, Joanne Xiu, Angela Ellerbrock, Sandeep K Reddy, Elias Obeid, Stephen V Liu, Aliccia Bollig-Fischer, Duska Separovic, Ari Vanderwalde
BACKGROUND/AIM: African Americans (AA) have the highest incidence and mortality of any racial/ethnic group in the US for most cancer types. Heterogeneity in the molecular biology of cancer, as a contributing factor to this disparity, is poorly understood. To address this gap in knowledge, we explored the molecular landscape of colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and high-grade glioma (HGG) from 271 AA and 636 Caucasian (CC) cases. MATERIALS AND METHODS: DNA from formalin-fixed paraffin-embedded tumors was sequenced using next-generation sequencing...
April 2018: Anticancer Research
Anca Macovei, Andrea Pagano, Maria Elisa Sabatini, Sofia Grandi, Alma Balestrazzi
The hTdp1 (human tyrosyl-DNA phosphodiesterase 1) inhibitor NSC120686 has been used, along with topoisomerase inhibitors, as a pharmacophoric model to restrain the Tdp1 activity as part of a synergistic treatment for cancer. While this compound has an end-point application in medical research, in plants, its application has not been considered so far. The originality of our study consists in the use of hTdp1 inhibitor in Medicago truncatula cells, which, unlike human cells, contain two Tdp1 genes. Hence, the purpose of this study was to test the hTdp1 inhibitor NSC120686 as an exploratory tool to investigate the plant Tdp1 genes, since their characterization is still in incipient phases...
March 28, 2018: Genes
Frédéric Jeannot, Thomas Taillier, Pierre Despeyroux, Stephane Renard, Astrid Rey, Michaël Mourez, Christoph Poeverlein, Imène Khichane, Marc-Antoine Perrin, Stéphanie Versluys, Robert A Stavenger, Jianzhong Huang, Thomas Germe, Anthony Maxwell, Sha Cao, Douglas L Huseby, Diarmaid Hughes, Eric Bacqué
In our quest for new antibiotics able to address the growing threat of multi-drug resistant infections caused by Gram-negative bacteria, we have investigated an unprecedented series of non-quinolone bacterial topoisomerase inhibitors from the Sanofi patrimony, named IPYs for ImidazoPYrazinones as part of the IMI ENABLE organization. Hybridization of these historical compounds with the quinazolinediones, a known series of topoisomerase inhibitors, led us to a novel series of tricyclic IPYs that demonstrated potential for broad spectrum activity, in vivo efficacy and a good developability profile although later profiling revealed a genotoxicity risk...
March 29, 2018: Journal of Medicinal Chemistry
Timothy J Wendorff, James M Berger
Type II topoisomerases manage DNA supercoiling and aid chromosome segregation using a complex, ATP-dependent duplex strand passage mechanism. Type IIB topoisomerases and their homologs support both archaeal/plant viability and meiotic recombination. Topo VI, a prototypical type IIB topoisomerase, comprises two Top6A and two Top6B protomers; how these subunits cooperate to engage two DNA segments and link ATP turnover to DNA transport is poorly understood. Using multiple biochemical approaches, we show that Top6B, which harbors the ATPase activity of topo VI, recognizes and exploits the DNA crossings present in supercoiled DNA to stimulate subunit dimerization by ATP...
March 29, 2018: ELife
Xin An, Fei Xu, Rongzhen Luo, Qiufan Zheng, Jiabin Lu, Yanhua Yang, Tao Qin, Zhongyu Yuan, Yanxia Shi, Wenqi Jiang, Shusen Wang
BACKGROUND: Topoisomerase II alpha (TOP2A) protein has been shown to be a proliferation marker associated with tumor grade and Ki67 index. The prognostic effect of TOP2A seems different among different subtypes of breast cancer. The current study evaluated the prognostic impact of TOP2A protein on luminal breast cancer. METHOD: Altogether 434 stage I-II luminal breast cancer patients who underwent curative surgery in Sun Yat-Sen University Cancer Center between 2007 and 2009 were enrolled...
March 27, 2018: BMC Cancer
Koji Ando, Yara Hamade Tohme, Adithi Srinivasiah, Julian Taylor-Parker, Yevgeniya Harrington, Ankur K Shah, Eiji Oki, Mohan Brahmandam, Ajit K Bharti
Phosphorylation is the most extensively studied posttranslational modification of proteins. There are approximately 500 kinases known in the human genome. The kinase-activated pathways regulate almost every aspect of cell function and a deregulated kinase cascade leads to impaired cellular function. Impaired regulation of several kinase cascades, including the epidermal growth factor receptor (EGFR) pathway, leading to tumor pathogenesis, is well documented. Thus, a phosphospecific test with prognostic or predictive value was expected in oncology...
March 1, 2018: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
Callum Walker, Sherif F El-Khamisy
Maintaining genomic stability constitutes a major challenge facing cells. DNA breaks can arise from direct oxidative damage to the DNA backbone, the inappropriate activities of endogenous enzymes such as DNA topoisomerases, or due to transcriptionally-derived RNA/DNA hybrids (R-loops). The progressive accumulation of DNA breaks has been linked to several neurological disorders. Recently, however, several independent studies have implicated nuclear and mitochondrial genomic instability, perturbed co-transcriptional processing, and impaired cellular clearance pathways as causal and intertwined mechanisms underpinning neurodegeneration...
March 23, 2018: Brain: a Journal of Neurology
Annabelle Congras, Nina Caillet, Nouritza Torossian, Cathy Quelen, Camille Daugrois, Pierre Brousset, Laurence Lamant, Fabienne Meggetto, Coralie Hoareau-Aveilla
Systemic anaplastic large-cell lymphoma (ALCL) is a childhood T cell neoplasm defined by the presence or absence of translocations that lead to the ectopic expression of anaplastic lymphoma kinase (ALK), with nucleophosmin-ALK (NPM-ALK) fusions being the most common. Polychemotherapy involving doxorubicin is the standard first-line treatment but for the 25 to 35% of patients who relapse and develop resistance the prognosis remains poor. We studied the potential role of the microRNA miR-125b in the development of resistance to doxorubicin in NPM-ALK(+) ALCL...
March 6, 2018: Oncotarget
Tian-Lu Wang, Ying-Qiu Song, Yang-Wu Ren, Bao-Sen Zhou, He-Tong Wang, Ya Gao, Hong Yu, Yu-Xia Zhao
Background: Nonsmall cell lung cancer (NSCLC) mainly contains adenocarcinoma (AC) and squamous cell carcinoma (SqCC). This study investigated single nucleotide polymorphism (SNP) of topoisomerase II alpha (TOP2A) and dual-specificity phosphatase 6 (DUSP6) in a hospital-based case and control cohort of individuals for association with risk of different histological subtypes of NSCLC. Materials and Methods: A total of 454 (237 SqCC and 217 AC) NSCLC patients, and 454 healthy controls were recruited for analysis of TOP2A rs471692 and DUSP6 rs2279574 genotypes using the TaqMan polymerase chain reaction technique...
2018: Journal of Cancer Research and Therapeutics
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