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https://www.readbyqxmd.com/read/28643177/targeting-dna-repair-and-replication-stress-in-the-treatment-of-ovarian-cancer
#1
REVIEW
Junko Murai
Approximately half of high-grade serous epithelial ovarian cancers incur alterations in genes of homologous recombination (BRCA1, BRCA2, RAD51C, Fanconi anemia genes), and the rest incur alterations in other DNA repair pathways at high frequencies. Such cancer-specific gene alterations can confer selective sensitivity to DNA damaging agents such as cisplatin and carboplatin, topotecan, etoposide, doxorubicin, and gemcitabine. Originally presumed to inhibit DNA repair, PARP inhibitors that have recently been approved by the FDA for the treatment of advanced ovarian cancer also act as DNA damaging agents by inducing PARP-DNA complexes...
June 22, 2017: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28642874/combination-treatment-with-ppar%C3%AE-ligand-and-its-specific-inhibitor-gw9662-downregulates-bis-and-14-3-3-gamma-inhibiting-stem-like-properties-in-glioblastoma-cells
#2
Chang-Nim Im
PPARγ is a nuclear receptor that regulates differentiation and proliferation and is highly expressed in many cancer cells. Its synthetic ligands, such as rosiglitazone and ciglitazone, and its inhibitor GW9662, were shown to induce cellular differentiation, inhibit proliferation, and lead to apoptosis. Glioblastoma is a common brain tumor with poor survival prospects. Recently, glioblastoma stem cells (GSCs) have been examined as a potential target for anticancer therapy; however, little is known about the combined effect of various agents on GSCs...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28642599/targeted-therapies-expanding-the-use-of-parp-inhibitors
#3
Sarah Seton-Rogers
No abstract text is available yet for this article.
June 23, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28642177/protective-functions-of-pj34-a-parp-inhibitor-is-related-to-down-regulation-of-calpain-and-nf-%C3%AE%C2%BAb-in-a-mouse-model-of-tbi
#4
Xiaogang Tao, Xuetao Chen, Zonggang Hou, Shuyu Hao, Baiyun Liu
OBJECTIVES: Poly(ADP-ribose) polymerase (PARP), calpain, and nuclear factor-κB (NF-κB) are reported to participate in inflammatory reactions in pathological conditions and are involved in traumatic brain injury. The objective of this study was to investigate whether PARP participated in inflammation related to calpain and NF-κB in a mouse model of controlled cortical impact (CCI). METHODS: PJ34 (10 mg/kg), a selective PARP inhibitor, was administered intraperitoneally 5 min and 8 h after experimental CCI...
June 19, 2017: World Neurosurgery
https://www.readbyqxmd.com/read/28640935/additive-effect-of-radiosensitization-by-2-deoxy-d-glucose-delays-dna-repair-kinetics-and-suppresses-cell-proliferation-in-oral-squamous-cell-carcinoma
#5
Mayumi Kawata, Kazuhiro Ogi, Koyo Nishiyama, Sho Miyamoto, Takafumi Nakagaki, Makoto Shimanishi, Akihiro Miyazaki, Hiroyoshi Hiratsuka
BACKGROUND: It has well known that, compared to normal cells, tumor cells have a different manner of energy metabolism, which influences the sensitivity of radiotherapy (RT). However, whether inhibition of glycolysis enhances the efficacy of radiotherapy is a matter of debate in oral squamous cell carcinoma (OSCC). The aim of this study was to characterize whether the combination of radiotherapy with the glucose inhibitor 2-deoxy-D-glucose (2-DG) affected DNA repair kinetics. METHODS: To compare the synergistic effect of 2-DG, we examined the cell survival after treatment with radiation, 2-DG and a combination of the two in 5 OSCC cell lines and one lip fibroblast cell line, determined using clonogenic survival assay...
June 22, 2017: Journal of Oral Pathology & Medicine
https://www.readbyqxmd.com/read/28638267/synergistic-antitumor-effect-of-sorafenib-in-combination-with-atm-inhibitor-in-hepatocellular-carcinoma-cells
#6
Jianhua Liu, Yahui Liu, Lingyu Meng, Bai Ji, Daqing Yang
Background: Currently, sorafenib is the only systemic chemotherapy drug for advanced stage Hepatocellular carcinoma (HCC). However, emerging data from some clinical HCC patients indicate that sorafenib alone has only moderate antitumor efficacy, and could not inhibit disease metastasis and progression. KU-55933 is a specific ATM inhibitor, which has pro-apoptotic effect on tumor cells. In this study, we analyzed the synergistic effect of sorafenib and KU-55933 on the proliferation of HCC cell lines. Methods: Three HCC cell lines were treated with sorafenib and KU-55933 alone or combination in vitro to investigate inhibitory effect by MTT and wound healing assay...
2017: International Journal of Medical Sciences
https://www.readbyqxmd.com/read/28631775/-innovations-in-the-treatment-of-ovarian-cancer-analysis-of-the-therapeutic-development-from-platinum-to-immunotherapy
#7
Gesuino Angius, Pierangela Sepe, Anselmo Papa, Silverio Tomao, Federica Tomao
Ovarian cancer is the seventh most common cancer in women. The therapeutic approach provides for an appropriate integration between surgery and chemotherapy. Surgery is an important step for diagnosis, staging and therapy, aiming at the complete cytoreduction of all macroscopic visible disease. At the moment, adjuvant and first-line chemotherapy has as a standard the carboplatin-paclitaxel combination. Further, the addition of bevacizumab in the advanced stage (IIIB-IV) is strongly recommended. Despite the initial effectiveness, however, 70-80% of patients develop relapsed disease within the first two years and require subsequent treatment lines that have palliative, rather than curative purposes and that seek to reach a chronic state for the disease...
June 2017: Recenti Progressi in Medicina
https://www.readbyqxmd.com/read/28628639/small-molecule-inhibitors-uncover-synthetic-genetic-interactions-of-human-flap-endonuclease-1-fen1-with-dna-damage-response-genes
#8
Thomas A Ward, Peter J McHugh, Stephen T Durant
Flap endonuclease 1 (FEN1) is a structure selective endonuclease required for proficient DNA replication and the repair of DNA damage. Cellularly active inhibitors of this enzyme have previously been shown to induce a DNA damage response and, ultimately, cell death. High-throughput screens of human cancer cell-lines identify colorectal and gastric cell-lines with microsatellite instability (MSI) as enriched for cellular sensitivity to N-hydroxyurea series inhibitors of FEN1, but not the PARP inhibitor olaparib or other inhibitors of the DNA damage response...
2017: PloS One
https://www.readbyqxmd.com/read/28627168/mitochondria-associated-apoptosis-in-human-melanoma-cells-induced-by-cardanol-monoene-from-cashew-nut-shell-liquid
#9
Wei-Chao Su, Yu-Feng Lin, Xiang-Ping Yu, Yu-Xia Wang, Xiao-Dong Lin, Qiao-Zhen Su, Dong-Yan Shen, Qing-Xi Chen
Cardanol monoene (CM) is the major phenolic component extracted from cashew nut shell liquid (CNSL), which has been relevant to wide range of biological effects. In this study, we found that CM could inhibit the M14 human melanoma cells proliferation in a dose dependent and time dependent manner, and the IC50 values were determined to be 23.15 ± 2.42 μM and 12.30 ± 1.67 μM after 24 h and 48 h treatment, respectively. The flow cytometric analysis demonstrated that CM induced M14 cell cycle arrest at S phase, along with the collapse of mitochondrial membrane potential (ΔΨm) and the accumulation of reactive oxygen species (ROS) level in cells,but the apoptotic cells reduced when treated with Z-VAD-FMK (pan-caspase inhibitor)...
June 19, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28625978/the-alkylating-chemotherapeutic-temozolomide-induces-metabolic-stress-in-idh1-mutant-cancers-and-potentiates-nad-depletion-mediated-cytotoxicity
#10
Kensuke Tateishi, Fumi Higuchi, Julie Miller, Mara V A Koerner, Nina Lelic, Ganesh M Shankar, Shota Tanaka, David E Fisher, Tracy Batchelor, A John Iafrate, Hiroaki Wakimoto, Andrew S Chi, Daniel P Cahill
IDH1-mutant gliomas are dependent upon the canonical coenzyme nicotinamide adenine dinucleotide (NAD+) for survival. It is known that Poly(ADP-ribose) polymerase (PARP) activation consumes NAD+ during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide (TMZ) could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of TMZ on NAD+ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to TMZ, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD+ biosynthesis...
June 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28625311/cancers-de-l%C3%A2-ovaire-brca-mut%C3%A3-consultation-d%C3%A2-oncog%C3%A3-n%C3%A3-tique-et-prescription-des-inhibiteurs-de-parp
#11
Laurence Gladieff, Dominique Stoppa Lyonnet, Alain Lortholary, Alexandra Leary, Catherine Genestie, Isabelle Ray-Coquard
GENETIC COUNSELING AND PARP INHIBITORS PRESCRIPTION: Upon the availability of the PARP inhibitors in relapsed ovarian carcinoma, the pathways of the oncogenetic counseling were modified. Any research for a constitutional alteration of the BRCA1 and BRCA2 genes must be accompanied by an oncogenetic counseling. BRCA testing is recommended from the diagnosis to every woman with an ovarian or fallopian tube or peritoneum of high grade adenocarcinoma, whatever the age at the diagnosis and her family history. In case of sensitive relapse or potential inclusion in a clinical trial and in the absence of preliminary constitutional research, the oncogenetic counseling is organized according to a fast track pathway and a somatic analysis can be realized in parallel...
May 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28625310/mise-%C3%A3-jour-2016-des-recommandations-pour-la-pratique-clinique-de-nice-saint-paul-de-vence-dans-le-cancer-de-l%C3%A2-ovaire-et-du-col-de-l%C3%A2-ut%C3%A3-rus-%C3%A3-un-stade-avanc%C3%A3
#12
Florence Joly, Denis Querleu, Moise Namer, Eric Pujade-Lauraine
UPDATED 2016 RECOMMENDATIONS FOR THE CLINICAL PRACTICE OF NICE/SAINT-PAUL-DE-VENCE IN OVARIAN CANCER AND ADVANCED CERVICAL CANCER: Since the first edition of the 2012-2013 Clinical Practice Recommendations Nice-Saint-Paul for gynecological cancers, the management of ovarian cancer has become more complex with a better definition of histological subtypes of ovarian cancers, the update of the anatomo-clinical classifications, the evolution of the recommended quality criteria for surgery. In addition, the integration of new medical options, such as PARP inhibitors, requires us to review our management of ovarian cnacer patients (including early systematic oncogenetic research of homologous recombination pathway deficiency)...
May 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28622906/discovery-of-novel-quinazoline-2-4-1h-3h-dione-derivatives-as-potent-parp-2-selective-inhibitors
#13
Hailong Zhao, Ming Ji, Guonan Cui, Jie Zhou, Fangfang Lai, Xiaoguang Chen, Bailing Xu
The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program...
May 26, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28619759/modelling-therapy-resistance-in-brca1-2-mutant-cancers
#14
Amy Dréan, Chris T Williamson, Rachel Brough, Inger Brandsma, Malini Menon, Asha Konde, Isaac Garcia-Murillas, Helen N Pemberton, Jessica Frankum, Rumana Rafiq, Nicholas Badham, James Campbell, Aditi Gulati, Nicholas C Turner, Stephen J Pettitt, Alan Ashworth, Christopher J Lord
Although PARP inhibitors target BRCA1 or BRCA2 mutant tumour cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in BRCA1 or BRCA2 Whether secondary mutant tumour cells are selected for in a Darwinian fashion by treatment is unclear. Furthermore, how PARP inhibitor resistance might be therapeutically targeted is also poorly understood. Using CRISPR-mutagenesis, we generated isogenic tumour cell models with secondary BRCA1 or BRCA2 mutations...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28615517/mtor-signaling-mediates-resistance-to-tankyrase-inhibitors-in-wnt-driven-colorectal-cancer
#15
Tetsuo Mashima, Yoko Taneda, Myung-Kyu Jang, Anna Mizutani, Yukiko Muramatsu, Haruka Yoshida, Ayana Sato, Noritaka Tanaka, Yoshikazu Sugimoto, Hiroyuki Seimiya
Activation of Wnt/β-catenin signaling is essential for colorectal carcinogenesis. Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, is a positive regulator of the Wnt/β-catenin signaling. Accordingly, tankyrase inhibitors are under preclinical development for colorectal cancer (CRC) therapy. However, Wnt-driven colorectal cancer cells are not equally sensitive to tankyrase inhibitors, and cellular factors that affect tankyrase inhibitor sensitivity remain elusive. Here, we established a tankyrase inhibitor-resistant cell line, 320-IWR, from Wnt/β-catenin-dependent CRC COLO-320DM cells...
May 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28615100/-the-mechanism-underlying-the-effects-of-tea-polyphenol-on-epirubicin-induced-autophagy-and-apoptosis-in-t24-bladder-cancer-cells
#16
Wen Gu, Hubin Yin, Yan Liu, Xin Gou
Objective To investigate the mechanism by which epirubicin (EPI) induces autophagy and the mechanism by which tea polyphenol (TP) regulates EPI-induced autophagy and apoptosis in T24 bladder cancer cells. Methods T24 cells weredivided into control group, EPI group, TP group and TP plus EPI group. Eight hours after corresponding treatments in different groups, transmission electron microscopy (TEM) was used to observe the image of autophagosomes. The expressions of autophagy-related protein LC3II and p62 in the cells were detected by Western blotting...
June 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/28614062/brca-mutations-in-the-manifestation-and-treatment-of-ovarian-cancer
#17
REVIEW
Zimin Pan, Xing Xie
BRCA genes are important for the integrity and stability of genetic material and play key roles in repairing DNA breaks via high fidelity homologous recombination. BRCA mutations are known to predispose carriers to gynecological malignancies, accounting for a majority of hereditary OC cases. Known to be lethal, OC is difficult to detect and control. Testing for BRCA mutations is a key step in the risk assessment, prognosis, treatment and prevention of OC and current clinical guidelines recommend BRCA mutation testing for all OCs of epithelial origin...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28611537/therapeutic-advances-and-new-directions-for-triple-negative-breast-cancer
#18
REVIEW
Eleni Andreopoulou, Catherine M Kelly, Hayley M McDaid
Triple-negative breast cancer (TNBC) is a molecularly diverse grouping with poor prognosis for which chemotherapy remains the foundation of treatment. The molecular heterogeneity of the disease rationalizes its diverse biological behavior and differential response to treatment. Estimates of up to 20% of patients diagnosed have germline mutations in DNA-damage repair-pathway genes, namely BRCA1 and 2, and this can be used to select patients likely to respond to platinums and/or inhibitors of poly(ADP-ribose) polymerase (PARP)...
March 2017: Breast Care
https://www.readbyqxmd.com/read/28610746/a-universal-genetic-testing-initiative-for-patients-with-high-grade-non-mucinous-epithelial-ovarian-cancer-and-the-implications-for-cancer-treatment
#19
Erica M Bednar, Holly D Oakley, Charlotte C Sun, Catherine C Burke, Mark F Munsell, Shannon N Westin, Karen H Lu
OBJECTIVE: Genetic counseling (GC) and germline genetic testing (GT) for BRCA1 and BRCA2 are considered standard of care for patients with high-grade, non-mucinous epithelial ovarian, fallopian tube, and primary peritoneal cancers (HGOC). We describe a universal genetic testing initiative to increase the rates of recommendation and acceptance of GC and GT to >80% for patients with HGOC at our institution. METHODS: Data from a consecutive cohort of patients seen in our gynecologic oncology clinics between 9/1/2012 and 8/31/2015 for evaluation of HGOC were retrospectively analyzed...
June 10, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28608237/exogenous-adipokine-peptide-resistin-protects-against-focal-cerebral-ischemia-reperfusion-injury-in-mice
#20
Jiangtao Zhu, Di Wu, Chenyu Zhao, Man Luo, Ronald C Hamdy, Balvin H L Chua, Xingshun Xu, Zhigang Miao
Previous studies have demonstrated that plasma resistin levels were increased in patients with acute ischemic stroke. However, the role of resistin after ischemic brain injury is still unclear. In this study, we investigated the protective effects of resistin on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model. We found that resistin (i.c.v.) significantly reduced infarct volume and improved neurological deficits after 45 min of ischemia and 24 h of reperfusion. Furthermore, our data demonstrate that intraperitoneal administration of resistin (10 µg/kg body weight) also had protective effects on infarct volume, indicating the crossing of resistin through the impaired BBB after ischemia injury...
June 12, 2017: Neurochemical Research
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