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https://www.readbyqxmd.com/read/28521333/drugging-the-cancers-addicted-to-dna-repair
#1
Jac A Nickoloff, Dennie Jones, Suk-Hee Lee, Elizabeth A Williamson, Robert Hromas
Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality)...
November 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28513990/network-meta-analysis-on-the-effects-of-dna-damage-response-related-gene-mutations-on-overall-survival-of-breast-cancer-based-on-tcga-database
#2
Chang Liu, Hong Chang, Xiao-Han Li, Ya-Fei Qi, Jin-Ou Wang, Ying Zhang, Xiang-Hong Yang
The study was conducted for comparing the effects of 12 DNA damage response gene mutations (CHEK1, CHEK2, RAD51, BRCA1, BRCA2, MLH1, MSH2, ATM, ATR, MDC1, PARP1 and FANCF) on the overall survival (OS) of breast cancer (BC) patients. We searched the Cancer Genome Atlas (TCGA) database from inception to September 2016. Studies that investigated the association between 12 DNA damage responses related genes and BC consolidated into this Network meta-analysis, by comparing directly or indirectly to evaluate the hazard rate (HR) value and the surface under the cumulative sequence ranking curves (SUCRA)...
May 17, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28513279/w09-a-novel-autophagy-enhancer-induces-autophagy-dependent-cell-apoptosis-via-activation-of-the-egfr-mediated-ras-raf1-map2k-mapk1-3-pathway
#3
Pinghu Zhang, Zuguo Zheng, Li Ling, Xiaohui Yang, Ni Zhang, Xue Wang, Maozhi Hu, Yu Xia, Yiwen Ma, Haoran Yang, Yunyi Wang, Hongqi Liu
The EGFR (epidermal growth factor receptor) signaling pathway is frequently deregulated in many malignancies. Therefore, targeting the EGFR pathway is regarded as a promising strategy for anticancer drug discovery. Herein, we identified a 2-amino-nicotinonitrile compound (w09) as a novel autophagy enhancer, which potently induced macroautophagy/autophagy and consequent apoptosis in gastric cancer cells. Mechanistic studies revealed that EGFR-mediated activation of the RAS-RAF1-MAP2K-MAPK1/3 signaling pathway played a critical role in w09-induced autophagy and apoptosis of gastric cancer cells...
May 17, 2017: Autophagy
https://www.readbyqxmd.com/read/28510338/therapeutic-targeting-of-poly-adp-ribose-polymerase-1-in-cancer-current-developments-therapeutic-strategies-and-future-opportunities
#4
REVIEW
Jyotika Rajawat, Nidhi Shukla, Durga Prasad Mishra
Poly(ADP-ribose) polymerase-1 (PARP1) is key protein involved in numerous cellular processes including DNA repair, replication, and transcription. PARP interacts directly, indirectly, or via PARylation with various oncogenic proteins and regulates several transcription factors, thereby modulating carcinogenesis. Therapeutic inhibition of PARP is therefore perceived as a promising anticancer strategy, and a number of PARP inhibitors (PARPi) are in different stages of clinical evaluation. PARPi inhibit the DNA repair pathway and thus form the concept of synthetic lethality in cancer therapeutics...
May 16, 2017: Medicinal Research Reviews
https://www.readbyqxmd.com/read/28487110/nf90-regulates-parp1-mrna-stability-in-hepatocellular-carcinoma
#5
Dan Song, Huixing Huang, Juanjuan Wang, Yahui Zhao, Xiaoding Hu, Funan He, Long Yu, Jiaxue Wu
Poly (ADP-ribose) polymerase 1 (PARP1) is an ADP- ribosylation enzyme and plays important roles in a variety of cellular processes, including DNA damage response and tumor development. However, the post-transcriptional regulation of PARP1 remains largely unknown. In this study, we identified that the mRNA of PARP1 is associated with nuclear factor 90 (NF90) by RNA immunoprecipitation plus sequencing (RIP-seq) assay. The mRNA and protein levels of PARP1 are dramatically decreased in NF90-depleted cells, and NF90 stabilizes PARP1's mRNA through its 3'UTR...
May 6, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28482792/poly-adp-ribosyl-polymerase-1-inhibitors-a-patent-review
#6
Mengda Cao, Xi Sun, Yanjun Zhou, Wen Huang, Ling Meng, Ji-Fu Wei
BACKGROUND: Poly (ADP-ribosyl) polymerase 1 (PARP1) is important in maintaining genomic stability, repairing DNA damage, and regulating transcriptional processes. Altered PARP1 activity is associated with a multitude of pathologies especially cancer. The broad application prospects of PARP1 inhibitors attract many well-known pharmaceutical companies, which promotes the development of PARP1 inhibitors. Objective:Present review aims to introduce PARP1 inhibitors by their structures and try to point out future development direction of PARP1 inhibitors...
May 8, 2017: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/28481869/the-transcription-factor-gata3-is-required-for-homologous-recombination-repair-by-regulating-ctip-expression
#7
F Zhang, H Tang, Y Jiang, Z Mao
GATA3, a critical transcription factor involved in the development of the mammary gland, also plays important roles in mammary tumorigenesis by regulating transcription in coordination with two essential DNA repair factors, PARP1 and BRCA1. However, whether and how GATA3 participates in the process of DNA repair, which is often associated with tumorigenesis, has not been investigated. Here we demonstrate that GATA3 is required for the repair of DNA double-strand breaks (DSBs) by homologous recominbation (HR)...
May 8, 2017: Oncogene
https://www.readbyqxmd.com/read/28481221/gene-expression-and-mutation-guided-synthetic-lethality-eradicates-proliferating-and-quiescent-leukemia-cells
#8
Margaret Nieborowska-Skorska, Katherine Sullivan, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Grazyna Hoser, Silvia Maifrede, Esteban Martinez, Daniela Di Marcantonio, Elisabeth Bolton-Gillespie, Kimberly Cramer-Morales, Jaewong Lee, Min Li, Artur Slupianek, Daniel Gritsyuk, Sabine Cerny-Reiterer, Ilona Seferynska, Tomasz Stoklosa, Lars Bullinger, Huaqing Zhao, Vera Gorbunova, Katarzyna Piwocka, Peter Valent, Curt I Civin, Markus Muschen, John E Dick, Jean C Y Wang, Smita Bhatia, Ravi Bhatia, Kolia Eppert, Mark D Minden, Stephen M Sykes, Tomasz Skorski
Quiescent and proliferating leukemia cells accumulate highly lethal DNA double-strand breaks that are repaired by 2 major mechanisms: BRCA-dependent homologous recombination and DNA-dependent protein kinase-mediated (DNA-PK-mediated) nonhomologous end-joining, whereas DNA repair pathways mediated by poly(ADP)ribose polymerase 1 (PARP1) serve as backups. Here we have designed a personalized medicine approach called gene expression and mutation analysis (GEMA) to identify BRCA- and DNA-PK-deficient leukemias either directly, using reverse transcription-quantitative PCR, microarrays, and flow cytometry, or indirectly, by the presence of oncogenes such as BCR-ABL1...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28462496/synthetic-lethal-targeting-of-rnf20-through-parp1-silencing-and-inhibition
#9
Brent J Guppy, Kirk J McManus
PURPOSE: The identification of novel therapeutic targets that exploit the aberrant genetics driving oncogenesis is critical to better combat cancer. RNF20 is somatically altered in numerous cancers, and its diminished expression drives genome instability, a driving factor of oncogenesis. Accordingly, we sought to determine whether PARP1 silencing and inhibition could preferentially kill RNF20-deficient cells using a synthetic lethal strategy. METHODS: RNF20 and PARP1 were silenced using RNAi-based approaches...
May 1, 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/28458579/mentha-arvensis-linn-mediated-green-silver-nanoparticles-trigger-caspase-9-dependent-cell-death-in-mcf7-and-mda-mb-231-cells
#10
Prajna Paramita Banerjee, Arindam Bandyopadhyay, Singapura Nagesh Harsha, Rudragoud S Policegoudra, Shelley Bhattacharya, Niranjan Karak, Ansuman Chattopadhyay
INTRODUCTION: Leaf extract of Mentha arvensis or mint plant was used as reducing agent for the synthesis of green silver nanoparticles (GSNPs) as a cost-effective, eco-friendly process compared to that of chemical synthesis. The existence of nanoparticles was characterized by ultraviolet-visible spectrophotometry, dynamic light scattering, Fourier transform infrared spectroscopy, X-ray diffraction, energy-dispersive X-ray analysis, atomic-force microscopy and transmission electron microscopy analyses, which ascertained the formation of spherical GSNPs with a size range of 3-9 nm...
2017: Breast Cancer: Targets and Therapy
https://www.readbyqxmd.com/read/28456626/compound-21-and-telmisartan-combination-mitigates-type-2-diabetic-nephropathy-through-amelioration-of-caspase-mediated-apoptosis
#11
Anuradha Pandey, Anil Bhanudas Gaikwad
The current study aimed to understand the role of novel, highly selective, orally active, non-peptide Angiotensin II type 2 receptor (AT2R) agonist, Compound 21 and its potential additive effect with Telmisartan on apoptosis and underlying posttranslational modifications in a non-genetic murine model for type 2 diabetic nephropathy (T2DN). An experimental model for T2DN was developed by administering low dose Streptozotocin in high fat diet fed male Wistar rats, followed by their treatment with Telmisartan, C21 or their combination...
June 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28456021/parp1-restricts-epstein-barr-virus-lytic-reactivation-by-binding-the-bzlf1-promoter
#12
Lena N Lupey-Green, Stephanie A Moquin, Kayla A Martin, Shane M McDevitt, Michael Hulse, Lisa B Caruso, Richard T Pomerantz, Jj L Miranda, Italo Tempera
The Epstein Barr virus (EBV) genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type, and in other herpesviruses, loss of CTCF binding at specific regions correlates with viral reactivation. Here, we demonstrate that binding of PARP1, an important cofactor of CTCF, at the BZLF1 lytic switch promoter restricts EBV reactivation. Knockdown of PARP1 in the Akata-EBV cell line significantly increases viral copy number and lytic protein expression...
April 26, 2017: Virology
https://www.readbyqxmd.com/read/28454547/parp1-expression-drives-the-synergistic-antitumor-activity-of-trabectedin-and-parp1-inhibitors-in-sarcoma-preclinical-models
#13
Ymera Pignochino, Federica Capozzi, Lorenzo D'Ambrosio, Carmine Dell'Aglio, Marco Basiricò, Marta Canta, Annalisa Lorenzato, Francesca Vignolo Lutati, Sandra Aliberti, Erica Palesandro, Paola Boccone, Danilo Galizia, Sara Miano, Giulia Chiabotto, Lucia Napione, Loretta Gammaitoni, Dario Sangiolo, Maria Serena Benassi, Barbara Pasini, Giovanna Chiorino, Massimo Aglietta, Giovanni Grignani
BACKGROUND: Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death...
April 28, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28446708/structural-and-functional-analysis-of-oceanobacillus-iheyensis-macrodomain-reveals-a-network-of-waters-involved-in-substrate-binding-and-catalysis
#14
Rubén Zapata-Pérez, Fernando Gil-Ortiz, Ana Belén Martínez-Moñino, Antonio Ginés García-Saura, Jordi Juanhuix, Álvaro Sánchez-Ferrer
Macrodomains are ubiquitous conserved domains that bind or transform ADP-ribose (ADPr) metabolites. In humans, they are involved in transcription, X-chromosome inactivation, neurodegeneration and modulating PARP1 signalling, making them potential targets for therapeutic agents. Unfortunately, some aspects related to the substrate binding and catalysis of MacroD-like macrodomains still remain unclear, since mutation of the proposed catalytic aspartate does not completely abolish enzyme activity. Here, we present a functional and structural characterization of a macrodomain from the extremely halotolerant and alkaliphilic bacterium Oceanobacillus iheyensis (OiMacroD), related to hMacroD1/hMacroD2, shedding light on substrate binding and catalysis...
April 2017: Open Biology
https://www.readbyqxmd.com/read/28443118/the-absence-of-the-arabidopsis-chaperone-complex-caf-1-produces-mitotic-chromosome-abnormalities-and-changes-in-the-expression-profiles-of-genes-involved-in-dna-repair
#15
Javier Varas, Juan L Santos, Mónica Pradillo
Chromatin Assembly Factor 1 (CAF-1) is an evolutionary conserved heterotrimeric chaperone complex that facilitates the incorporation of histones H3 and H4 onto newly synthesized DNA. We demonstrate here that the mutant deficient for the large subunit of the complex, fas1-4, and in minor extent, the mutant deficient for the middle subunit, fas2-1, display chromosome abnormalities throughout Arabidopsis mitosis. Among them, we observed multicentromeric chromosomes at metaphase, and chromatid bridges and acentric fragments at anaphase-telophase...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28442756/crystal-structure-based-discovery-of-a-novel-synthesized-parp1-inhibitor-ol-1-with-apoptosis-inducing-mechanisms-in-triple-negative-breast-cancer
#16
Leilei Fu, Shuya Wang, Xuan Wang, Peiqi Wang, Yaxin Zheng, Dahong Yao, Mingrui Guo, Lan Zhang, Liang Ouyang
Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28442322/in-vitro-and-in-vivo-antitumor-activities-of-t-3764518-a-novel-and-orally-available-small-molecule-stearoyl-coa-desaturase-1-inhibitor
#17
Satoru Nishizawa, Hiroyuki Sumi, Yoshihiko Satoh, Yukiko Yamamoto, Satoshi Kitazawa, Kohei Honda, Hideo Araki, Kazuyo Kakoi, Keisuke Imamura, Masako Sasaki, Ikuo Miyahisa, Yoshinori Satomi, Ryuuichi Nishigaki, Megumi Hirayama, Kazunobu Aoyama, Hironobu Maezaki, Takahito Hara
Most cancer cells are characterized by elevated lipid biosynthesis. The rapid proliferation of cancer cells requires de novo synthesis of fatty acids. Stearoyl-CoA desaturase-1 (SCD1), a key enzyme for lipogenesis, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. Therefore, it has been studied as a candidate target for cancer therapy. In this study, we demonstrate the pharmacological properties of T-3764518, a novel and orally available small molecule inhibitor of SCD1...
April 22, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28439984/effects-of-energy-supply-and-nicotinic-acid-supplementation-on-serum-anti-oxidative-capacity-and-on-expression-of-oxidative-stress-related-genes-in-blood-leucocytes-of-periparturient-primi-and-pluriparous-dairy-cows
#18
S Bühler, J Frahm, R Tienken, S Kersten, U Meyer, K Huber, S Dänicke
The periparturient period is accompanied by metabolic and oxidative stress. Niacin is known to decrease lipolysis but is also reported to have anti-oxidative effects. Therefore, we examined the effects of energy supply and a nicotinic acid (NA) supplementation on anti-oxidative serum parameters and on the expression of oxidative stress-related genes in blood leucocytes of periparturient dairy cows, differing in parity. Twenty-nine pluriparous and 18 primiparous cows were allocated to four different feeding groups 42 days before expected parturition until 100 days postpartum and fed a ration with either a low concentrate proportion of 30% (LC) or a high concentrate proportion of 60% (HC)...
April 25, 2017: Journal of Animal Physiology and Animal Nutrition
https://www.readbyqxmd.com/read/28439535/a-murine-preclinical-syngeneic-transplantation-model-for-breast-cancer-precision-medicine
#19
Lorenzo Federico, Zechen Chong, Dong Zhang, Daniel J McGrail, Wei Zhao, Kang Jin Jeong, Christopher P Vellano, Zhenlin Ju, Mihai Gagea, Shuying Liu, Shreya Mitra, Jennifer B Dennison, Philip L Lorenzi, Robert Cardnell, Lixia Diao, Jing Wang, Yiling Lu, Lauren A Byers, Charles M Perou, Shiaw-Yih Lin, Gordon B Mills
We previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. We have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model...
April 2017: Science Advances
https://www.readbyqxmd.com/read/28432356/a-role-of-human-rnase-p-subunits-rpp29-and-rpp21-in-homology-directed-repair-of-double-strand-breaks
#20
Enas R Abu-Zhayia, Hanan Khoury-Haddad, Noga Guttmann-Raviv, Raphael Serruya, Nayef Jarrous, Nabieh Ayoub
DNA damage response (DDR) is needed to repair damaged DNA for genomic integrity preservation. Defective DDR causes accumulation of deleterious mutations and DNA lesions that can lead to genomic instabilities and carcinogenesis. Identifying new players in the DDR, therefore, is essential to advance the understanding of the molecular mechanisms by which cells keep their genetic material intact. Here, we show that the core protein subunits Rpp29 and Rpp21 of human RNase P complex are implicated in DDR. We demonstrate that Rpp29 and Rpp21 depletion impairs double-strand break (DSB) repair by homology-directed repair (HDR), but has no deleterious effect on the integrity of non-homologous end joining...
April 21, 2017: Scientific Reports
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