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PARP inhibitors

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https://www.readbyqxmd.com/read/28723922/temporal-progression-of-parp-activity-in-the-prph2-mutant-rd2-mouse-neuroprotective-effects-of-the-parp-inhibitor-pj34
#1
Ayse Sahaboglu, Alaa Sharif, Lili Feng, Enver Secer, Eberhart Zrenner, François Paquet-Durand
Peripherin (peripherin/rds) is a membrane-associated protein that plays a critical role in the morphogenesis of rod and cone photoreceptor outer segments. Mutations in the corresponding PRPH2 gene cause different types of retinal dystrophies characterized by a loss of photoreceptors. Over activation of poly-ADP-ribose polymerase (PARP) was previously shown to be involved in different animal models for hereditary retinal dystrophies. This includes the rd2 mouse, which suffers from a human homologous mutation in the PRPH2 gene...
2017: PloS One
https://www.readbyqxmd.com/read/28723660/poly-adp-ribose-polymerase-inhibitors-as-radiosensitizers-a-systematic-review-of-pre-clinical-and-clinical-human-studies
#2
REVIEW
Paul Lesueur, François Chevalier, Jean-Baptiste Austry, Waisse Waissi, Hélène Burckel, Georges Noël, Jean-Louis Habrand, Yannick Saintigny, Florence Joly
BACKGROUND: Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality...
July 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28723622/dual-targeting-of-mdm2-and-bcl2-as-a-therapeutic-strategy-in-neuroblastoma
#3
Alan Van Goethem, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Frank Speleman, Jason Shohet, Jo Vandesompele, Tom Van Maerken
Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28721808/molecular-tests-for-the-choice-of-cancer-therapy
#4
Anna P Sokolenko, Evgeny N Imyanitov
There are over a dozen of approved cancer drugs, whose administration is tailored to predictive laboratory tests. The examples include estrogen and progesterone receptor status determination for the use of endocrine therapy, HER2 assessment for the administration of HER2-targeting agents, EGFR and ALK gene testing for lung cancer treatment, BRAF analysis in melanoma, etc. While first predictive tests relied on relatively easy laboratory procedures, more recent developments require rather sophisticated assays...
July 19, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28719017/contrasting-sirtuin-and-parp-activity-of-selected-2-4-6-trisubstituted-benzimidazoles
#5
Keng Yoon Yeong, Soo Choon Tan, Chun-Wai Mai, Chee-Onn Leong, Felicia Fei-Lei Chung, Yean Kee Lee, Chin Fei Chee, Noorsaadah Abdul Rahman
Both sirtuin and poly(ADP-ribose)polymerase (PARP) family of enzymes utilize NAD+ as co-substrate. Inhibitors of sirtuins and PARPs are important tools in drug discovery as they are reported to be linked to multiple diseases such as cancer. New potent sirtuin inhibitors (2,4,6-trisubstituted benzimidazole) were discovered from reported PARP inhibitor scaffold. Interestingly, the synthesized compounds have contrasting sirtuin and PARP-1 inhibitory activity. We showed that modification on benzimidazoles may alter their selectivity towards sirtuin or PARP-1 enzymes...
July 18, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28714471/progression-through-mitosis-promotes-parp-inhibitor-induced-cytotoxicity-in-homologous-recombination-deficient-cancer-cells
#6
Pepijn M Schoonen, Francien Talens, Colin Stok, Ewa Gogola, Anne Margriet Heijink, Peter Bouwman, Floris Foijer, Madalena Tarsounas, Sohvi Blatter, Jos Jonkers, Sven Rottenberg, Marcel A T M van Vugt
Mutations in homologous recombination (HR) genes BRCA1 and BRCA2 predispose to tumorigenesis. HR-deficient cancers are hypersensitive to Poly (ADP ribose)-polymerase (PARP) inhibitors, but can acquire resistance and relapse. Mechanistic understanding how PARP inhibition induces cytotoxicity in HR-deficient cancer cells is incomplete. Here we find PARP inhibition to compromise replication fork stability in HR-deficient cancer cells, leading to mitotic DNA damage and consequent chromatin bridges and lagging chromosomes in anaphase, frequently leading to cytokinesis failure, multinucleation and cell death...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28713983/malformin%C3%A2-a1-treatment-alters-invasive-and-oncogenic-phenotypes-of-human-colorectal-cancer-cells-through-stimulation-of-the-p38-signaling-pathway
#7
Sun-Young Park, Hyung-Hoon Oh, Young-Lan Park, Hyung-Min Yu, Dae-Seong Myung, Sung-Bum Cho, Wan-Sik Lee, Daeho Park, Young-Eun Joo
Malformin A1 (MA1), a cyclic pentapeptide isolated from Aspergillus niger, has been found to possess a range of bioactive properties including antibacterial activity. However, it is unclear whether MA1 exerts an anticancer effect or not. In this study, we conducted in vitro experiments to investigate its anticancer properties in human colorectal cancer cells. The effect of MA1 on human colorectal cancer cells, SW480 and DKO1, was examined by the WST-1 cell viability assay, inverted microscopy, 5-bromo-2-deoxyuridine (BrdU) incorporation, flow cytometry, DNA fragmentation, wound healing, Transwell assays, and western blotting...
July 10, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28713932/human-trypsin-inhibitor-reduces-the-apoptosis-of-lipopolysaccharide%C3%A2-induced-human-kidney%C3%A2-2-cells-by-promoting-mitochondrial-fusion
#8
Ning Liu, Zhiyi Jiang, Yongjun Liu, Yao Nie, Juan Chen, Bin Ouyang, Xiangdong Guan, Minying Chen
Imbalance in mitochondrial fusion/fission is one of the mechanisms leading to sepsis‑induced mitochondrial dysfunction and cell apoptosis. The present study examined the effects of human trypsin inhibitor (UTI), a well‑known antioxidant and anti‑inflammatory substance, on mitochondrial dynamics and cell apoptosis in lipopolysaccharide (LPS)‑induced human kidney‑2 (HK‑2) cells. The HK‑2 cells were incubated for 24 h either with LPS (800 ng/ml) or LPS (800 ng/ml) mixed with UTI (250 U/ml). Cell viability was assessed using a3‑(4,5‑dimethyl‑2‑thiazolyl)‑2, 5‑diphenyl‑2‑H‑tetrazolium bromide assay...
July 5, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28713919/ganetespib-induces-g2-m-cell-cycle-arrest-and-apoptosis-in-gastric-cancer-cells-through-targeting-of-receptor-tyrosine-kinase-signaling
#9
Harry Lee, Nipun Saini, Amanda B Parris, Ming Zhao, Xiaohe Yang
Heat shock protein 90 (HSP90) regulates several important cellular processes via its repertoire of 'client proteins'. These client proteins have been found to play fundamental roles in signal transduction, cell proliferation, cell cycle progression and survival, as well as other features of malignant cells, such as invasion, tumor angiogenesis and metastasis. Thus, HSP90 is an emerging target for cancer therapy. To this end, we evaluated ganetespib (STA-9090), a novel and potent HSP90 inhibitor, for its activity in gastric cancer cell lines...
July 13, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28713892/trichostatin%C3%A2-a-induces-bladder-cancer-cell-death-via-intrinsic-apoptosis-at-the-early%C3%A2-phase-and-sp1%C3%A2-survivin-downregulation-at-the-late%C3%A2-phase-of-treatment
#10
Shou-Chieh Wang, Shou-Tsung Wang, Hung-Te Liu, Xiang-Yu Wang, She-Ching Wu, Lei-Chin Chen, Yi-Wen Liu
Histone deacetylase (HDAC) inhibitors have been widely shown to result in cancer cell death. The present study investigated the mechanisms underlying the antitumor effects of the phytochemical trichostatin A (TSA), a classic pan-HDAC inhibitor, in 5,637 urinary bladder cancer cells. It was found that TSA caused cell cycle arrest at the G2/M and G1 phase accompanied by reduced expression of cyclin D1 and upregulated induction of p21. In addition, TSA induced morphological changes, reduced cell viability and apoptotic cell death in 5,637 cells through caspase-3 activation followed by PARP cleavage...
July 6, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28713162/abt-263-induces-g1-g0-phase-arrest-apoptosis-and-autophagy-in-human-esophageal-cancer-cells-in-vitro
#11
Qing-Huan Lin, Fu-Chang Que, Chun-Ping Gu, De-Sheng Zhong, Dan Zhou, Yi Kong, Le Yu, Shu-Wen Liu
Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT-263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl-2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms...
July 17, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28706968/brca1-reversion-mutation-acquired-after-treatment-identified-by-liquid-biopsy
#12
Paul Mayor, Laurie M Gay, Shashikant Lele, Julia A Elvin
•Secondary, reversion mutations in BRCA genes can restore protein function.•Reversion mutations can underlie resistance to therapies such as PARP inhibitors.•Reversion mutations arise during the course of treatment.
August 2017: Gynecologic Oncology Reports
https://www.readbyqxmd.com/read/28705099/heat-induced-brca2-degradation-in-human-tumors-provides-rationale-for-hyperthermia-parp-inhibitor-combination-therapies
#13
Nathalie van den Tempel, Hanny Odijk, Netteke van Holthe, Kishan Naipal, Anja Raams, Berina Eppink, Dik van Gent, Jose Hardillo, Gerda Verduijn, Jan Drooger, Gerard van Rhoon, Dineke Smedts, Helena van Doorn, Joost Boormans, Agnes Jager, Martine Franckena, Roland Kanaar
PURPOSE: Hyperthermia (40-44°C) effectively sensitizes tumors to radiotherapy by locally altering tumor biology. One of the effects of heat at the cellular level is inhibition of DNA repair by homologous recombination via degradation of the BRCA2-protein. This suggests that hyperthermia can expand the group of patients that benefit from PARP-inhibitors, a drug exploiting homologous recombination deficiency. Here, we explore whether the molecular mechanisms that cause heat-mediated degradation of BRCA2 are conserved in cell lines from various origins and, most importantly, whether, BRCA2 protein levels can be attenuated by heat in freshly biopted human tumors...
July 13, 2017: International Journal of Hyperthermia
https://www.readbyqxmd.com/read/28704451/targeting-of-x-linked-inhibitor-of-apoptosis-protein-and-pi3-kinase-akt-signaling-by-embelin-suppresses-growth-of-leukemic-cells
#14
Kirti S Prabhu, Kodappully S Siveen, Shilpa Kuttikrishnan, Ahmad Iskandarani, Magdalini Tsakou, Iman W Achkar, Lubna Therachiyil, Roopesh Krishnankutty, Aijaz Parray, Michal Kulinski, Maysaloun Merhi, Said Dermime, Ramzi M Mohammad, Shahab Uddin
The X-linked inhibitor of apoptosis (XIAP) is a viable molecular target for anticancer drugs that overcome apoptosis-resistance of malignant cells. XIAP is an inhibitor of apoptosis, mediating through its association with BIR3 domain of caspase 9. Embelin, a quinone derivative isolated from the Embelia ribes plant, has been shown to exhibit chemopreventive, anti-inflammatory, and apoptotic activities via inhibiting XIAP activity. In this study, we found that embelin causes a dose-dependent suppression of proliferation in leukemic cell lines K562 and U937...
2017: PloS One
https://www.readbyqxmd.com/read/28700980/aurora-a-kinase-regulates-non-homologous-end-joining-and-poly-adp-ribose-polymerase-function-in-ovarian-carcinoma-cells
#15
Thuy-Vy Do, Jeff Hirst, Stephen Hyter, Katherine F Roby, Andrew K Godwin
Ovarian cancer is usually diagnosed at late stages when cancer has spread beyond the ovary and patients ultimately succumb to the development of drug-resistant disease. There is an urgent and unmet need to develop therapeutic strategies that effectively treat ovarian cancer and this requires a better understanding of signaling pathways important for ovarian cancer progression. Aurora A kinase (AURKA) plays an important role in ovarian cancer progression by mediating mitosis and chromosomal instability. In the current study, we investigated the role of AURKA in regulating the DNA damage response and DNA repair in ovarian carcinoma cells...
July 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28699513/parp-inhibitor-drugs-in-the-treatment-of-breast-ovarian-prostate-and-pancreatic-cancers-an-update-of-clinical-trials
#16
Dalia Kamel, Christopher Gray, Jagdeeb Walia, Vikaash Kumar
PARP inhibitors appear to offer a promising role in the accompaniment of many of the cytotoxic agents used in the present day to combat cancer proliferation in BRCA1/2 deficient tumors. Current species of PARP inhibitors have yet to demonstrate a superior effect to that of existing therapies when administered as a single agent; however, they have appeared to amplify the effect of these existing chemotherapies when utilized together. This suggests that PARP inhibitors could play an effective maintenance role in current cancer-combating strategies...
July 11, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28698968/inhibition-of-poly-adp-ribose-polymerase-1-enhances-gene-expression-of-selected-sirtuins-and-app-cleaving-enzymes-in-amyloid-beta-cytotoxicity
#17
Przemysław L Wencel, Walter J Lukiw, Joanna B Strosznajder, Robert Piotr Strosznajder
Poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs) are involved in the regulation of cell metabolism, transcription, and DNA repair. Alterations of these enzymes may play a crucial role in Alzheimer's disease (AD). Our previous results indicated that amyloid beta (Aβ) peptides and inflammation led to activation of PARP1 and cell death. This study focused on a role of PARP1 in the regulation of gene expression for SIRTs and beta-amyloid precursor protein (βAPP) cleaving enzymes under Aβ42 oligomers (AβO) toxicity in pheochromocytoma cells (PC12) in culture...
July 12, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28698869/effects-of-poly-adp-ribose-polymerase-1-inhibition-in-a-neonatal-rodent-model-of-hypoxic-ischemic-injury
#18
Melanie Klöfers, Jules Kohaut, Ivo Bendix, Josephine Herz, Vinzenz Boos, Ursula Felderhoff-Müser, Mark Dzietko
BACKGROUND: Hypoxia ischemia (HI) to the developing brain occurs in 1-6 in 1000 live births. Large numbers of survivors have neurological long-term sequelae. However, mechanisms of recovery after HI are not understood and preventive measures or clinical treatments are not effective. Poly(ADP-ribose) polymerase-1 is overactivated in response to ischemia. In neonatal mice HI activates PARP-1 but its role in perinatal brain injury remains uncertain. OBJECTIVE: Aim of this study was to explore the effect of TES448 (PARP-1-inhibitor) and hypothermia after an ischemic insult...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28698806/epigallocatechin-3-gallate-enhances-er-stress-induced-cancer-cell-apoptosis-by-directly-targeting-parp16-activity
#19
Juanjuan Wang, Chenggang Zhu, Dan Song, Ruiqi Xia, Wenbo Yu, Yongjun Dang, Yiyan Fei, Long Yu, Jiaxue Wu
Poly(ADP-ribose) polymerases (PARPs) are ADP-ribosylating enzymes and play important roles in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, a poly-ADP-ribose transferase, and suffer from poor selectivity. PARP16, a mono-ADP-ribose transferase, has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Here we newly characterized epigallocatechin-3-gallate (EGCG) as a potential inhibitor of PARP16...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28695525/purification-of-dna-damage-dependent-parps-from-e-coli-for-structural-and-biochemical-analysis
#20
Marie-France Langelier, Jamin D Steffen, Amanda A Riccio, Michael McCauley, John M Pascal
Human PARP-1, PARP-2, and PARP-3 are key players in the cellular response to DNA damage, during which their catalytic activities are acutely stimulated through interaction with DNA strand breaks. There are also roles for these PARPs outside of the DNA damage response, most notably for PARP-1 and PARP-2 in the regulation of gene expression. Here, we describe a general method to express and purify these DNA damage-dependent PARPs from E. coli cells for use in biochemical assays and for structural and functional analysis...
2017: Methods in Molecular Biology
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