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PARP inhibitors

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https://www.readbyqxmd.com/read/29453076/development-of-novel-synthesized-phthalazinone-based-parp-1-inhibitors-with-apoptosis-inducing-mechanism-in-lung-cancer
#1
Hadia Almahli, Elie Hadchity, Maiy Y Jaballah, Racha Daher, Hazem A Ghabbour, Maha M Kabil, Nasser S Al-Shakliah, Wagdy M Eldehna
Herein we report the synthesis of two series of 4-phenylphthalazin-1-ones 11a-i and 4- benzylphthalazin-1-ones 16a-h as anti-lung adenocarcinoma agents with potential inhibitory activity against PARP-1. All the newly synthesized phthalazinones were evaluated for their anti-proliferative activity against A549 lung carcinoma cell line. Phthalazinones 11c-i and 16b, c showed significant cytotoxic activity against A549 cells at different concentrations (0.1, 1 and 10 μM) for two time intervals (24 h and 48 h)...
February 7, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29446719/dna-double-strand-breaks-repair-inhibitors-relevance-as-potential-new-anticancer-therapeutics
#2
Paulina Kopa, Anna Macieja, Grzegorz Galita, Zbigniew J Witczak, Tomasz Poplawski
DNA Double-strand breaks are considered one of the most lethal form of DNA damage. Many effective anticancer therapeutic approaches used chemical and physical methods to generate DNA double-strand breaks in the cancer cells. They include: IR and drugs which mimetic its action, topoisomerase poisons, some alkylating agents or drugs which affected DNA replication process. On the other hand, cancer cells are mostly characterized by highly effective systems of DNA damage repair. There are two main DNA repair pathways used to fix double-strand breaks: NHEJ and HRR...
February 13, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29436682/fatostatin-suppresses-growth-and-enhances-apoptosis-by-blocking-srebp-regulated-metabolic-pathways-in-endometrial-carcinoma
#3
Shuhong Gao, Zhengzheng Shi, Xin Li, Wenzhi Li, Yiling Wang, Zhiming Liu, Jie Jiang
Fatostatin, a chemical inhibitor of the sterol regulatory element‑binding protein (SREBP) pathway, has been reported to possess high antitumor activity against prostate and pancreatic cancer. The main aim of the present study was to investigate the effects and mechanism of fatostatin in endometrial carcinoma (EC). In the present study, we determined that fatostatin inhibited EC cell viability and colony formation capacity, decreased the invasive and migratory capacities of EC cells, induced EC cell cycle arrest at the G2/M phase and stimulated caspase‑mediated apoptosis of EC cells...
February 13, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29436674/the-targeted-inhibition-of-hsp90-by-a-synthetic-small-molecule-dpide-offers-an-effective-treatment-strategy-against-tnbcs
#4
Yong Jin Oh, Sun You Park, Young Ho Seo
Triple-negative breast cancers (TNBCs) are the most aggressive and metastatic subtype of breast cancers and exhibit poor clinical outcome due to the lack of drug target receptors such as estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (Her2). The limited effectiveness of therapeutic options and the poor prognosis of TNBC patients emphasize the urgent need for identifying new therapeutic agents. In this regard, heat shock protein 90 (Hsp90) has emerged as a promising therapeutic target for the treatment of TNBCs...
February 7, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29435178/inhibition-of-the-mek-erk-pathway-augments-nab-paclitaxel-based-chemotherapy-effects-in-preclinical-models-of-pancreatic-cancer
#5
Niranjan Awasthi, Sheena Monahan, Alexis Stefaniak, Margaret A Schwarz, Roderich E Schwarz
Nab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29435156/cis-trimethoxy-resveratrol-induces-intrinsic-apoptosis-via-prometaphase-arrest-and-prolonged-cdk1-activation-pathway-in-human-jurkat-t-cells
#6
Chae Eun Kim, Do Youn Jun, Jong-Sik Kim, Young Ho Kim
Cis-trimethoxy resveratrol (cis-3M-RES) induced dose-dependent cytotoxicity and apoptotic DNA fragmentation in Jurkat T cell clones (JT/Neo); however, it induced only cytostasis in BCL-2-overexpressing cells (JT/BCL-2). Treatment with 0.25 μM cis-3M-RES induced G2/M arrest, BAK activation, Δψm loss, caspase-9 and caspase-3 activation, and poly (ADP-ribose) polymerase (PARP) cleavage in JT/Neo cells time-dependently but did not induce these events, except G2/M arrest, in JT/BCL-2 cells. Moreover, cis-3M-RES induced CDK1 activation, BCL-2 phosphorylation at Ser-70, MCL-1 phosphorylation at Ser-159/Thr-163, and BIM (BIMEL and BIML) phosphorylation irrespective of BCL-2 overexpression...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29435141/induction-of-endoplasmic-reticulum-stress-and-mitochondrial-dysfunction-dependent-apoptosis-signaling-pathway-in-human-renal-cancer-cells-by-norcantharidin
#7
Min-Hua Wu, Hui-Ling Chiou, Chu-Liang Lin, Ching-Yi Lin, Shun-Fa Yang, Yi-Hsien Hsieh
Previous studies reported that norcantharidin (NCTD) has anti-tumor effects. We investigated the antitumor effects and underlying mechanism of NCTD on human renal cancer in vitro and in vivo. NCTD significantly decreased renal cancer cell viability by induction of apoptosis, as determined by the MTT assay and annexin V/PI staining. NCTD treatment of 786-O and A-498 cells altered the expression of caspase family proteins and PARP. Moreover, NCTD induced mitochondrial depolarization, which was accompanied by an increased level of Bax and decreased levels of Bcl-2 and Mcl-1...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29435132/suppression-of-homology-dependent-dna-double-strand-break-repair-induces-parp-inhibitor-sensitivity-in-vhl-deficient-human-renal-cell-carcinoma
#8
Susan E Scanlon, Denise C Hegan, Parker L Sulkowski, Peter M Glazer
The von Hippel-Lindau ( VHL ) tumor suppressor gene is inactivated in the vast majority of human clear cell renal carcinomas. The pathogenesis of VHL loss is currently best understood to occur through stabilization of the hypoxia-inducible factors, activation of hypoxia-induced signaling pathways, and transcriptional reprogramming towards a pro-angiogenic and pro-growth state. However, hypoxia also drives other pro-tumorigenic processes, including the development of genomic instability via down-regulation of DNA repair gene expression...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29429804/clinical-outcome-of-prostate-cancer-patients-with-germline-dna-repair-mutations-retrospective-analysis-from-an-international-study
#9
Joaquin Mateo, Heather H Cheng, Himisha Beltran, David Dolling, Wen Xu, Colin C Pritchard, Helen Mossop, Pasquale Rescigno, Raquel Perez-Lopez, Verena Sailer, Michael Kolinsky, Ada Balasopoulou, Claudia Bertan, David M Nanus, Scott T Tagawa, Heather Thorne, Bruce Montgomery, Suzanne Carreira, Shahneen Sandhu, Mark A Rubin, Peter S Nelson, Johann S de Bono
BACKGROUND: Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear. OBJECTIVE: To determine whether gDDRm status impacts benefit from established therapies in mPC. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status...
January 29, 2018: European Urology
https://www.readbyqxmd.com/read/29427345/crosstalk-of-dna-double-strand-break-repair-pathways-in-parp-inhibitor-treatment-of-brca1-2-mutated-cancer
#10
REVIEW
Shigeaki Sunada, Akira Nakanishi, Yoshio Miki
Germ-line mutations in breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) significantly increase cancer risk in hereditary breast and ovarian cancer syndrome (HBOC). Both genes function in the homologous recombination (HR) pathway of DNA double-strand break (DSB) repair process. Therefore, the DNA-repair defect characteristic in cancer cells brings therapeutic advantage for Poly(ADP-ribose) polymerase (PARP) inhibitor-induced synthetic lethality. The PARP inhibitor-based therapeutics initially causes cancer lethality but acquired resistance mechanisms have been found and need to be elucidated...
February 10, 2018: Cancer Science
https://www.readbyqxmd.com/read/29425588/saponins-isolated-from-schizocapsa-plantaginea-inhibit-human-hepatocellular-carcinoma-cell-growth-in-vivo-and-in-vitro-via-mitogen-activated-protein-kinase-signaling
#11
Yue-Wen Sun, Han-Chen Qiu, Ming-Chun Ou, Run-Li Chen, Gang Liang
The underground cane of Schizocapsa plantaginea (Hance) has long been used by Chinese ethnic minority as a constituent of anti-cancer formulae. Saponins are abundant secondary metabolic products located in the underground cane of this plant. The potential therapeutic effects of total saponins isolated from Schizocapsa plantaginea (Hance) (SSPH) on human hepatocellular carcinoma (HCC) were tested in vitro in human liver cancer cell lines, SMMC-7721 and Bel-7404. Apoptosis and cell cycle arrest were determined using flow cytometry, caspase activation was determined by ELISA, and PARP, cleaved PARP, mitogen-activated protein kinase (MAPK) expression and phosphorylation were measured using Western blotting analysis...
January 2018: Chinese Journal of Natural Medicines
https://www.readbyqxmd.com/read/29423093/combination-of-a-hypomethylating-agent-and-inhibitors-of-parp-and-hdac-traps-parp1-and-dnmt1-to-chromatin-acetylates-dna-repair-proteins-down-regulates-nurd-and-induces-apoptosis-in-human-leukemia-and-lymphoma-cells
#12
Benigno C Valdez, Yang Li, David Murray, Yan Liu, Yago Nieto, Richard E Champlin, Borje S Andersson
Combination of drugs that target different aspects of aberrant cellular processes is an efficacious treatment for hematological malignancies. Hypomethylating agents (HMAs) and inhibitors of poly(ADP-ribose) polymerases (PARPis) and histone deacetylases (HDACis) are clinically active anti-tumor drugs. We hypothesized that their combination would be synergistically cytotoxic to leukemia and lymphoma cells. Exposure of AML and lymphoma cell lines to the combination of the PARPi niraparib (Npb), the HMA decitabine (DAC) and the HDACi romidepsin (Rom) or panobinostat (Pano) synergistically inhibited cell proliferation by up to 70% via activation of the ATM pathway, increased production of reactive oxygen species, decreased mitochondrial membrane potential, and activated apoptosis...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29416738/parp-1-inhibitors-sensitize-hnscc-cells-to-apr-246-by-inactivation-of-thioredoxin-reductase-1-trxr1-and-promotion-of-ros-accumulation
#13
Zhi-Xian Yin, Wei Hang, Gang Liu, Yi-Shu Wang, Xiang-Feng Shen, Qian-Hui Sun, Dong-Dong Li, Yong-Ping Jian, Yang-He Zhang, Cheng-Shi Quan, Qinghua Zeng, Yu-Lin Li, Rui-Xun Zhao, Qiang Ding, Zhi-Xiang Xu
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Mutations of TP53 may reach 70% - 85% in HNSCC patients without human papillomavirus (HPV) infection. Recurrence rate remains particularly high for HNSCC patients with mutations in the TP53 gene although patients are responsive to surgery, irradiation, and chemotherapy early in the treatment. p53-Reactivation and Induction of Massive Apoptosis-1 (PRIMA-1) and its methylated analogue PRIMA-1 Met (also known as APR-246) are quinuclidine compounds that rescue the DNA-binding activity of mutant p53 (mut-p53) and restore the potential of wild-type p53...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29416656/propranolol-enhanced-the-anti-tumor-effect-of-sunitinib-by-inhibiting-proliferation-and-inducing-g0-g1-s-phase-arrest-in-malignant-melanoma
#14
Xinwei Kuang, Min Qi, Cong Peng, Chengfang Zhou, Juan Su, Weiqi Zeng, Hong Liu, Jianglin Zhang, Mingliang Chen, Minxue Shen, Xiaoyun Xie, Fangfang Li, Shuang Zhao, Qingling Li, Zhongling Luo, Junchen Chen, Juan Tao, Yijing He, Xiang Chen
Both sunitinib, a multi-target tyrosine kinase inhibitor (TKI) and propranolol, a non-selective β-blocker, have proven therapeutic effects on malignant melanoma (MM). This study reports a synergistic effect of propranolol and sunitinib upon A375, P8 MM cell lines and mice xenografts. Cell viability assays detected a significant decrease of sunitinib IC50 in combination with propranolol, which was confirmed by a colony formation assay. Western blot showed that propranolol and sunitinib combination significantly down-regulated phospho-Rb, phospho-ERK, Cyclin D1, and Cyclin E, but had no effect on Bax, Bcl-2, or cleaved PARP expression...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29414646/morin-hydrate-ameliorates-cisplatin-induced-er-stress-inflammation-and-autophagy-in-hek-293-cells-and-mice-kidney-via-parp-1-regulation
#15
Mahendra Pal Singh, Anil Kumar Chauhan, Sun Chul Kang
The present study assessed the possible therapeutic potential of a natural flavonoid morin hydrate (MH), against cisplatin (CP) induced toxicity in HEK-293 cells and mice kidney. Herein, we observed that exposure of HEK-293 cells to CP (20 μM, 24 h) reduced the cell viability, and increased the intracellular ROS generation, nuclear DNA damage, Ca++ release, and accumulation of acidic vacuoles. Concomitantly, acute exposure of CP (30 mg/kg, 72 h) to male ICR mice induced histopathological changes in kidney tissue, and alterations in serum creatinine and blood urea nitrogen (BUN) levels...
February 1, 2018: International Immunopharmacology
https://www.readbyqxmd.com/read/29414021/development-and-validation-of-a-high-performance-liquid-chromatography-method-for-the-quantitation-of-intracellular-parp-inhibitor-olaparib-in-cancer-cells
#16
Pierre Daumar, Robin Dufour, Clémence Dubois, Frédérique Penault-Llorca, Mahchid Bamdad, Emmanuelle Mounetou
Olaparib is a potent PARP inhibitor in clinical use for cancer therapy. A bioanalytical assay was developed and validated for quantitation of intracellular level of olaparib in cells exposed to the drug. The assay involves an optimized and straightforward sample pretreatment with acetonitrile for olaparib solubilization, cell lysis and protein precipitation, and a high performance liquid chromatography (HPLC) method with ultraviolet detection. Several parameters in both the sample preparation and the detection steps were investigated...
January 30, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29413957/2-chlorohexadecanoic-acid-induces-er-stress-and-mitochondrial-dysfunction-in-brain-microvascular-endothelial-cells
#17
Eva Bernhart, Nora Kogelnik, Jürgen Prasch, Benjamin Gottschalk, Madeleine Goeritzer, Maria Rosa Depaoli, Helga Reicher, Christoph Nusshold, Ioanna Plastira, Astrid Hammer, Günter Fauler, Roland Malli, Wolfgang F Graier, Ernst Malle, Wolfgang Sattler
Peripheral leukocytes induce blood-brain barrier (BBB) dysfunction through the release of cytotoxic mediators. These include hypochlorous acid (HOCl) that is formed via the myeloperoxidase-H2O2-chloride system of activated phagocytes. HOCl targets the endogenous pool of ether phospholipids (plasmalogens) generating chlorinated inflammatory mediators like e.g. 2-chlorohexadecanal and its conversion product 2-chlorohexadecanoic acid (2-ClHA). In the cerebrovasculature these compounds inflict damage to brain microvascular endothelial cells (BMVEC) that form the morphological basis of the BBB...
January 5, 2018: Redox Biology
https://www.readbyqxmd.com/read/29413287/parp-inhibition-combined-with-thoracic-irradiation-exacerbates-esophageal-and-skin-toxicity-in-c57bl6-mice
#18
Luiza Madia Lourenco, Yanyan Jiang, Neele Drobnitzky, Marcus Green, Fiona Cahill, Agata Patel, Yasmin Shanneik, John Moore, Anderson J Ryan
PURPOSE: Poly (ADP-ribose) polymerase (PARP) inhibitors have been shown to enhance the radiosensitivity of cancer cells in vitro in a replication-dependent manner. Their in vivo radiosensitizing effects have also been demonstrated in preclinical tumor models. However, whether PARP inhibition can enhance the response to radiation therapy in normal tissues has been largely neglected. We hypothesized that PARP inhibition might also potentiate the response of replicating normal tissues to radiation therapy...
March 1, 2018: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/29412166/efflux-inhibition-by-iwr-1-endo-confers-sensitivity-to-doxorubicin-effects-in-osteosarcoma-cells
#19
Carl T Gustafson, Tewodros Mamo, Avudaiappan Maran, Michael J Yaszemski
Osteosarcoma is the most common bone tumor that affects children and young adults. Despite advances in the use of combination chemotherapy regimens, response to neoadjuvant chemotherapy in osteosarcoma remains a key determinant of patient outcome. Recently, highly potent small molecule inhibitors of canonical Wnt signaling through the poly(ADP-ribose) polymerase (PARP)-family enzymes, tankyrases 1 & 2 (Tnks1/2), have been considered as possible chemotherapy sensitizing agents. The goal of this study was to determine the ability of the highly specific Tnks1/2 inhibitor IWR-1-endo to sensitize chemotherapy-resistant osteosarcoma to doxorubicin...
February 2, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29409480/contrasting-roles-of-h3k4me3-and-h3k9me3-in-regulation-of-apoptosis-and-gemcitabine-resistance-in-human-pancreatic-cancer-cells
#20
Chunwan Lu, Dafeng Yang, Maria E Sabbatini, Aaron H Colby, Mark W Grinstaff, Nicholas H Oberlies, Cedric Pearce, Kebin Liu
BACKGROUND: Pancreas ductal adenocarcinoma (PDAC) has the most dismal prognosis among all human cancers since it is highly resistant to chemotherapy, radiotherapy and immunotherapy. The anticipated consequence of all therapies is induction of tumor apoptosis. The highly resistance nature of PDACs to all therapies suggests that the intrinsic tumor cell factors, likely the deregulated apoptosis pathway, are key mechanisms underlying PDAC non-response to these therapies, rather than the therapeutic agents themselves...
February 6, 2018: BMC Cancer
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