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https://www.readbyqxmd.com/read/27926532/novel-parp1-2-inhibitor-mefuparib-hydrochloride-elicits-potent-in-vitro-and-in-vivo-anticancer-activity-characteristic-of-high-tissue-distribution
#1
Jin-Xue He, Meng Wang, Xia-Juan Huan, Chuan-Huizi Chen, Shan-Shan Song, Ying-Qing Wang, Xue-Mei Liao, Cun Tan, Qian He, Lin-Jiang Tong, Yu-Ting Wang, Xiao-Hua Li, Yi Su, Yan-Yan Shen, Yi-Ming Sun, Xin-Ying Yang, Yi Chen, Zhi-Wei Gao, Xiao-Yan Chen, Bing Xiong, Xiu-Lian Lu, Jian Ding, Chun-Hao Yang, Ze-Hong Miao
The approval of poly(ADP-ribose) polymerase (PARP) inhibitor AZD2281 in 2014 marked the successful establishment of the therapeutic strategy targeting homologous recombination repair defects of cancers in the clinic. However, AZD2281 has poor water solubility, low tissue distribution and relatively weak in vivo anticancer activity, which appears to become limiting factors for its clinical use. In this study, we found that mefuparib hydrochloride (MPH) was a potent PARP inhibitor, possessing prominent in vitro and in vivo anticancer activity...
December 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27925196/sirt1-sirt3-axis-regulates-cellular-response-to-oxidative-stress-and-etoposide
#2
Ilaria Carnevale, Laura Pellegrini, Patrizia D'Aquila, Serena Saladini, Emanuela Lococo, Lucia Polletta, Enza Vernucci, Eleonora Foglio, Stefano Coppola, Luigi Sansone, Giuseppe Passarino, Dina Bellizzi, Matteo A Russo, Massimo Fini, Marco Tafani
Sirtuins are conserved NAD+-dependent deacylases. SIRT1 is a nuclear and cytoplasmic sirtuin involved in the control of histones a transcription factors function. SIRT3 is a mitochondrial protein, which regulates mitochondrial function. Although both SIRT1 and SIRT3 have been implicated in resistance to cellular stress, the link between these two sirtuins has not been studied so far. Here we aimed to unravel: i) the role of SIRT1-SIRT3 axis for cellular response to oxidative stress and DNA damage; ii) how mammalian cells modulate such SIRT1-SIRT3 axis and which mechanisms are involved...
December 7, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27924151/effect-of-sp600125-on-the-mitotic-spindle-in-hela-cells-leading-to-mitotic-arrest-endoreduplication-and-apoptosis
#3
Donia Mili, Kaouthar Abid, Imed Rjiba, Abderraouf Kenani
BACKGROUND: The JNK inhibitor SP600125 strongly inhibits cell proliferation in many human cancer cells by blocking mitosis progression and inducing cell death. Despite, all this study, the mechanism by which SP600125 inhibits mitosis-related effects in human cervical cells (HeLa cells) remains unclear. In this study, we investigated the effects of SP600125 on the cell viability, cell cycle, and on the spindle assembly during mitosis in HeLa cells. METHODS: To explore this approach, we used a viability test, an immunofluorescence microscopy to detect Histone phosphorylation and mitotic spindle aberrations...
2016: Molecular Cytogenetics
https://www.readbyqxmd.com/read/27924011/roles-for-aprin-pds5b-in-homologous-recombination-and-in-ovarian-cancer-prediction
#4
Anthony M Couturier, Hubert Fleury, Anne-Marie Patenaude, Victoria L Bentley, Amélie Rodrigue, Yan Coulombe, Joshi Niraj, Joris Pauty, Jason N Berman, Graham Dellaire, Javier M Di Noia, Anne-Marie Mes-Masson, Jean-Yves Masson
APRIN (PDS5 cohesin associated factor B) interacts with both the cohesin complex and the BRCA2 tumor suppressor. How APRIN influences cohesion and DNA repair processes is not well understood. Here, we show that APRIN is recruited to DNA damage sites. We find that APRIN interacts directly with RAD51, PALB2 and BRCA2. APRIN stimulates RAD51-mediated DNA strand invasion. APRIN also binds DNA with an affinity for D-loop structures and single-strand (ss) DNA. APRIN is a new homologous recombination (HR) mediator as it counteracts the RPA inhibitory effect on RAD51 loading to ssDNA...
October 24, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27922674/2-hydroxycinnamaldehyde-induces-apoptosis-through-hsf1-mediated-bag3-expression
#5
Hai-Anh Nguyen, Soo-A Kim
BAG3, a member of BAG co-chaperone family, is induced by stressful stimuli such as heat shock and heavy metals. Through interaction with various binding partners, BAG3 is thought to play a role in cellular adaptive responses against stressful conditions in normal and neoplastic cells. 2'-Hydroxycinnamaldehyde (HCA) is a natural derivative of cinnamaldehyde and has antitumor activity in various cancer cells. In the present study, for the first time, we identified that HCA induced BAG3 expression and BAG3-mediated apoptosis in cancer cells...
December 6, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27922187/tomentosin-induces-telomere-shortening-and-caspase-dependant-apoptosis-in-cervical-cancer-cells
#6
Nawel Merghoub, Hassan El Btaouri, Laila Benbacer, Saïd Gmouh, Chantal Trentesaux, Bertrand Brassart, Mohammed Attaleb, Claudie Madoulet, Thomas Wenner, Saaid Amzazi, Hamid Morjani, Mohamed El Mzibri
Tomentosin, a natural sesquiterpene lactone purified from of Inula viscosa L., was investigated for its anti-proliferative, telomere shortening and apoptotic effects on human cervical cancer HeLa and SiHa cell lines. Tomentosin was found to inhibit the growth of SiHa and HeLa cell lines in dose and time-dependent manner (IC50 values of 7.10 ± 0.78µM and 5.87 ± 0.36µM, respectively after 96h of treatment). As evidenced by TTAGGG telomere length assay, tomentosin target specifically the telomeric overhang lengthening...
December 6, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27920426/crystal-structure-based-discovery-of-a-novel-synthesized-parp1-inhibitor-ol-1-with-apoptosis-inducing-mechanisms-in-triple-negative-breast-cancer
#7
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 2016: Scientific Reports
https://www.readbyqxmd.com/read/27919953/bishydroquinone-renieramycin-m-induces-apoptosis-of-human-lung-cancer-cells-through-a-mitochondria-dependent-pathway
#8
Tatchakorn Pinkhien, Arnatchai Maiuthed, Supakarn Chamni, Khanit Suwanborirux, Naoki Saito, Pithi Chanvorachote
BACKGROUND: Renieranycin M (RM), a bistetrahydro-isoquinolinequinone isolated from the Thai blue sponge, Xestospongia sp. was reported to be a potent anti-lung cancer agent. Modification at quinone ring enhanced apoptosis over necrosis. Thus, bishydroquinone renieramycin M (HQ-RM) was prepared and evaluated for apoptosis induction in lung cancer cells. METHODS: HQ-RM was examined for cytotoxicity and apoptosis induction in human lung cancer H292 cells by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazoliumbromide and Hoechst/propidium iodide staining, respectively...
December 2016: Anticancer Research
https://www.readbyqxmd.com/read/27919945/the-leloir-pathway-of-galactose-metabolism-a-novel-therapeutic-target-for-hepatocellular-carcinoma
#9
Manshu Tang, Enoabasi Etokidem, Kent Lai
Hepatocellular carcinoma (HCC) is one of the most lethal types of cancer worldwide, with poor prognosis and limited treatments. In order to identify novel therapeutic targets that will lead to development of effective therapies with manageable side effects, we tested the hypothesis that knocking-down galactokinase (GALK1) or galactose-1 phosphate uridylyltransferase (GALT) gene expression would control the growth of cultured hepatoma cells. Our results showed small interfering RNA (siRNA) against GALK1 or GALT inhibited the growth of HepG2 cells in culture...
December 2016: Anticancer Research
https://www.readbyqxmd.com/read/27919448/fx11-inhibits-aerobic-glycolysis-and-growth-of-neuroblastoma-cells
#10
Eric J Rellinger, Brian T Craig, Alexandra L Alvarez, Haley L Dusek, Kwang W Kim, Jingbo Qiao, Dai H Chung
BACKGROUND: The MYC family of proteins promotes neuroblastoma tumorigenesis at least in part through the induction of aerobic glycolysis by promoting the transcription of key glycolytic enzymes, such as LDHA. FX11 is a selective inhibitor of LDHA that has demonstrated preclinical efficacy in adult cancers. Herein, we hypothesized that FX11 would inhibit aerobic glycolysis and block growth of neuroblastoma cells. METHODS: We surveyed 3 MYCN-single copy and 5 MYCN-amplified neuroblastoma cell lines to correlate C-MYC/N-MYC protein levels with LDHA expression...
December 2, 2016: Surgery
https://www.readbyqxmd.com/read/27918638/small-molecule-microarray-based-discovery-of-parp14-inhibitors
#11
Bo Peng, Ann-Gerd Thorsell, Tobias Karlberg, Herwig Schüler, Shao Q Yao
Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20-fold selectivity over PARP1...
December 5, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27918558/quantitating-drug-target-engagement-in-single-cells-in-vitro-and-in-vivo
#12
J Matthew Dubach, Eunha Kim, Katherine Yang, Michael Cuccarese, Randy J Giedt, Labros G Meimetis, Claudio Vinegoni, Ralph Weissleder
Quantitation of drug target engagement in single cells has proven to be difficult, often leaving unanswered questions in the drug development process. We found that intracellular target engagement of unlabeled new therapeutics can be quantitated using polarized microscopy combined with competitive binding of matched fluorescent companion imaging probes. We quantitated the dynamics of target engagement of covalent BTK inhibitors, as well as reversible PARP inhibitors, in populations of single cells using a single companion imaging probe for each target...
December 5, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27915154/lipopolysaccharides-stimulated-macrophage-products-enhance-withaferin-a-induced-apoptosis-via-activation-of-caspases-and-inhibition-of-nf-%C3%AE%C2%BAb-pathway-in-human-cancer-cells
#13
Liang Piao, Zhao Canguo, Lu Wenjie, Cheng Xiaoli, Shi Wenli, Lu Li
Macrophages, as a major cellular component in tumor microenvironment, play an important role in tumor progression. However, their roles in modulation of cytotoxic chemotherapy are still not fully understood. Here, we investigated the influence of Lipoplysaccharides (LPS)-stimulated macrophage products (LSMP) on Withaferin A (WA), a natural compound that derived from the medicinal plant Withania somnifera, as an antitumor agent in human breast cancer cells MDA-MB-231 and prostate cancer cells PC-3. Our results revealed that LSMP may enhance WA-induced apoptosis in both cell lines, the underlying mechanisms of which are closely associated with activation of caspase-8, -9 and -3, cleavage of poly ADP-ribose polymerase (PARP), as well as specifically inhibiting the translocation of nuclear factor-κB (NF-κB) and down-regulation of anti-apoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and inhibitor of apoptosis protein (cIAP1/2)...
December 1, 2016: Molecular Immunology
https://www.readbyqxmd.com/read/27909720/tetrandrine-inhibits-glioma-stem-like-cells-by-repressing-%C3%AE-catenin-expression
#14
Yong Zhang, Yu-Lin Wen, Ji-Wei Ma, Jie-Cheng Ye, Xiao Wang, Jian-Xian Huang, Chao-Yue Meng, Xiao-Ze Xu, Shao-Xiang Wang, Xue-Yun Zhong
Cancer stem cells (CSCs) in glioma are often responsible for relapse and resistance to therapy. The purpose of the present study was to confirm the self-renewal and migration inhibitory effects of tetrandrine (Tet), which is a compound extracted from the dried root of Stephania tetrandra S. Moore, toward glioma stem-like cells (GSLCs) and to examine the associated molecular mechanisms. Using a neurosphere culture technique, we enriched the GSLC population from the human glioblastoma cell lines U87 and U251...
November 23, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27908594/rucaparib-in-relapsed-platinum-sensitive-high-grade-ovarian-carcinoma-ariel2-part-1-an-international-multicentre-open-label-phase-2-trial
#15
Elizabeth M Swisher, Kevin K Lin, Amit M Oza, Clare L Scott, Heidi Giordano, James Sun, Gottfried E Konecny, Robert L Coleman, Anna V Tinker, David M O'Malley, Rebecca S Kristeleit, Ling Ma, Katherine M Bell-McGuinn, James D Brenton, Janiel M Cragun, Ana Oaknin, Isabelle Ray-Coquard, Maria I Harrell, Elaina Mann, Scott H Kaufmann, Anne Floquet, Alexandra Leary, Thomas C Harding, Sandra Goble, Lara Maloney, Jeff Isaacson, Andrew R Allen, Lindsey Rolfe, Roman Yelensky, Mitch Raponi, Iain A McNeish
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. METHODS: ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA...
November 28, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27908593/progress-in-parp-inhibitors-beyond-brca-mutant-recurrent-ovarian-cancer
#16
Antonio González Martín
No abstract text is available yet for this article.
November 28, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27904474/poly-adp-ribose-polymerase-inhibition-reveals-a-potential-mechanism-to-promote-neuroprotection-and-treat-neuropathic-pain
#17
REVIEW
Prashanth Komirishetty, Aparna Areti, Ranadeep Gogoi, Ramakrishna Sistla, Ashutosh Kumar
Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that limit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially peroxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly(ADP-ribose) polymerase (PARP) upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death...
October 2016: Neural Regeneration Research
https://www.readbyqxmd.com/read/27903423/cytotoxicity-of-trans-chalcone-and-licochalcone-a-against-breast-cancer-cells-is-due-to-apoptosis-induction-and-cell-cycle-arrest
#18
Luis Felipe Buso Bortolotto, Flávia Regina Barbosa, Gabriel Silva, Tamires Aparecida Bitencourt, Rene Oliveira Beleboni, Seung Joon Baek, Mozart Marins, Ana Lúcia Fachin
Chalcones are precursors of flavonoids that exhibit structural heterogeneity and potential antitumor activity. The objective of this study was to characterize the cytotoxicity of trans-chalcone and licochalcone A (LicoA(1)) against a breast cancer cell line (MCF-7) and normal murine fibroblasts (3T3). Also the mechanisms of the anti-cancer activity of these two compounds were studied. The alkaline comet assay revealed dose-dependent genotoxicity, which was more responsive against the tumor cell line, compared to the 3T3 mouse fibroblast cell line...
November 27, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27901267/binge-alcohol-intake-after-hypergravity-stress-sustainably-decreases-ampk-and-transcription-factors-necessary-for-hepatocyte-survival
#19
Sang Gil Lee, Hong Min Wu, Chan Gyu Lee, Choong Sik Oh, So Won Chung, Sang Geon Kim
BACKGROUND: Binge alcohol consumption elicits mitochondrial dysfunction in hepatocytes. An understanding of the effect of ethanol (EtOH) exposure after hypergravity stress on liver function may assist in the implementation of pathophysiological countermeasures for aerospace missions. This study investigated whether a combination of hypergravity stress and binge alcohol intake has a detrimental effect on AMP-activated protein kinase (AMPK) and other molecules necessary for hepatocyte survival...
November 30, 2016: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/27899771/-perspectives-of-individualized-treatment-by-genome-wide-analyses-in-ovarian-cancer
#20
Noriomi Matsumura, Ken Yamaguchi, Ryusuke Murakami, Masaki Mandai, Ikuo Konishi
Genome-wide analyses have recently been reported for ovarian cancer. High-grade serous ovarian carcinoma(HGSOC) almost exclusively harbor TP53 mutations and prominent copy number aberrations. Approximately 20% of HGSOCs harbor BRCA mutations, in which case PARP inhibitors may be effective. HGSOCs are classified into 4 molecular subtypes with distinct histopathological features by transcriptional profiling. These subtypes differ in prognosis and drug sensitivity. Additionally, a whole-genome analysis for HGSOC has revealed various factors that can induce resistance to chemotherapy...
November 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
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