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https://www.readbyqxmd.com/read/28723660/poly-adp-ribose-polymerase-inhibitors-as-radiosensitizers-a-systematic-review-of-pre-clinical-and-clinical-human-studies
#1
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/28700980/aurora-a-kinase-regulates-non-homologous-end-joining-and-poly-adp-ribose-polymerase-function-in-ovarian-carcinoma-cells
#2
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/28695500/quantification-of-parp-activity-in-human-tissues-ex-vivo-assays-in-blood-cells-and-immunohistochemistry-in-human-biopsies
#3
Eszter M Horvath, Zsuzsanna K Zsengellér, Csaba Szabo
Poly(ADP-ribosyl)ation of proteins is a posttranslational modification mediated by poly(ADP-ribose) polymerases (PARPs) that use NAD(+) as substrate to form the negatively charged polymer of poly(ADP-ribose) (PAR). After DNA damage, PARP-1 is responsible for approximately 90% of the total cellular PARylation activity. Numerous studies showed activation of PARP-1 in various conditions associated with oxidative and nitrosative stress, such as ischemia-reperfusion injury, diabetes mellitus, and inflammation, and also proved the beneficial effects of PARP inhibitors...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28692916/discovery-mechanism-and-metabolism-studies-of-2-3-difluorophenyl-linker-containing-parp1-inhibitors-with-enhanced-in%C3%A2-vivo-efficacy-for-cancer-therapy
#4
Wenhua Chen, Ne Guo, Minghui Qi, Haiying Dai, Minghuang Hong, Longfei Guan, Xiajuan Huan, Shanshan Song, Jinxue He, Yingqing Wang, Yong Xi, Xinying Yang, Yanyan Shen, Yi Su, Yiming Sun, Yinglei Gao, Yi Chen, Jian Ding, Yun Tang, Guobin Ren, Zehong Miao, Jian Li
Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1...
June 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28692638/the-first-nationwide-multicenter-prevalence-study-of-germline-brca1-and-brca2-mutations-in-chinese-ovarian-cancer-patients
#5
Xiaohua Wu, Lingying Wu, Beihua Kong, Jihong Liu, Rutie Yin, Hao Wen, Ning Li, Hualei Bu, Yanling Feng, Qingli Li, Xuesong Lu, Jia Wei, Xuehua Zhu, John Mills, Gillian Ellison, Thorsten Gutjahr, Yuzhen Liu
OBJECTIVE: Subjects with germline BRCA1/2 mutations (gBRCAm) have an increased risk of developing ovarian cancer and enhanced sensitivity to platinum-containing agents and PARP (poly[ADP-ribose] polymerase) inhibitors. BRCA mutations in Asian patients are poorly understood compared with other populations. We aimed to investigate gBRCAm prevalence and characteristics in Chinese ovarian cancer patients. METHODS: We conducted the first nationwide multicenter gBRCAm prevalence study in China...
July 7, 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/28676700/the-multifaceted-roles-of-parp1-in-dna-repair-and-chromatin-remodelling
#6
REVIEW
Arnab Ray Chaudhuri, André Nussenzweig
Cells are exposed to various endogenous and exogenous insults that induce DNA damage, which, if unrepaired, impairs genome integrity and leads to the development of various diseases, including cancer. Recent evidence has implicated poly(ADP-ribose) polymerase 1 (PARP1) in various DNA repair pathways and in the maintenance of genomic stability. The inhibition of PARP1 is therefore being exploited clinically for the treatment of various cancers, which include DNA repair-deficient ovarian, breast and prostate cancers...
July 5, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28665051/a-phase-1-dose-escalation-study-of-single-agent-veliparib-in-japanese-patients-with-advanced-solid-tumors
#7
Tadaaki Nishikawa, Koji Matsumoto, Kenji Tamura, Hiroyuki Yoshida, Yuichi Imai, Aki Miyasaka, Takuma Onoe, Satoshi Yamaguchi, Chikako Shimizu, Kan Yonemori, Tatsunori Shimoi, Mayu Yunokawa, Hao Xiong, Silpa Nuthalapati, Hideyuki Hashiba, Tsukasa Kiriyama, Terri Leahy, Philip Komarnitsky, Keiichi Fujiwara
Veliparib (ABT-888) is a potent, orally bioavailable poly(ADP-ribose) polymerase-1 and -2 inhibitor. This phase 1 study evaluated the tolerability, pharmacokinetic profile, safety, and preliminary antitumor activity of single-agent veliparib in Japanese patients with advanced solid tumors. Eligible patients were assigned to treatment with veliparib at 200 mg or 400 mg dose; veliparib was self-administered orally twice daily on days 1-28 of 28-day cycles. Dose escalation, following a 3+3 design, defined dose-limiting toxicities, the maximum tolerated dose, and the recommended phase 2 dose...
June 30, 2017: Cancer Science
https://www.readbyqxmd.com/read/28658642/folic-acid-conjugated-polymeric-micelles-loaded-with-a-curcumin-difluorinated-analog-for-targeting-cervical-and-ovarian-cancers
#8
Duy Luong, Prashant Kesharwani, Hashem O Alsaab, Samaresh Sau, Subhash Padhye, Fazlul H Sarkar, Arun K Iyer
The current study utilizes folic acid conjugated poly(styrene-co-maleic anhydride) block copolymer (FA-SMA) to enhance the solubility of a hydrophobic but very potent synthetic curcumin-difluorinated (CDF) analog and its targeted delivery to folate receptor-alpha overexpressing cancers. The nanomicelles showed high aqueous solubility. Importantly, the encapsulation of CDF in nanomicelles resulted in high photo-stability of the otherwise photo-labile drug. When the nanomicelles were tested in folate-receptor overexpressing ovarian and cervical cancer cells they exhibited high anticancer activity causing significant cell population to undergo apoptosis due to upregulation of tumor suppressor phosphatase and tensin homolog (PTEN) and inhibition of nuclear factor kappa-B (NFκB), which further confirmed the targeting ability and anticancer potentials of folate-targeted formulations...
June 21, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28650468/mkp-1-suppresses-parp-1-degradation-to-mediate-cisplatin-resistance
#9
J Wang, D H Kho, J-Y Zhou, R J Davis, G S Wu
Understanding the mechanisms of platinum compound resistance, including cisplatin resistance, has important implications for improving cancer treatments. Previous studies identified a potential role for mitogen-activated protein kinase phosphatase-1 (MKP-1) in cisplatin resistance. This work focuses on the regulation of poly(ADP-ribose) polymerase-1 (PARP-1) expression by MKP-1. We found that MKP-1 overexpression stimulates PARP-1 and poly(ADP-ribose) (PAR) protein expression and cisplatin resistance while its downregulation suppresses PARP-1 and PAR protein expression and cisplatin resistance...
June 26, 2017: Oncogene
https://www.readbyqxmd.com/read/28624626/alternative-polyadenylation-patterns-for-novel-gene-discovery-and-classification-in-cancer
#10
Oguzhan Begik, Merve Oyken, Tuna Cinkilli Alican, Tolga Can, Ayse Elif Erson-Bensan
Certain aspects of diagnosis, prognosis, and treatment of cancer patients are still important challenges to be addressed. Therefore, we propose a pipeline to uncover patterns of alternative polyadenylation (APA), a hidden complexity in cancer transcriptomes, to further accelerate efforts to discover novel cancer genes and pathways. Here, we analyzed expression data for 1045 cancer patients and found a significant shift in usage of poly(A) signals in common tumor types (breast, colon, lung, prostate, gastric, and ovarian) compared to normal tissues...
July 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28609289/adverse-eff-ects-of-polymeric-nanoparticle-poly-ethylene-glycol-block-polylactide-methyl-ether-peg-b-pla-on-steroid-hormone-secretion-by-porcine-granulosa-cells
#11
Sona Scsukova, Mlynarcikova A Bujnakova, A Kiss, E Rollerova
OBJECTIVES: Development of nanoparticles (NPs) for biomedical applications, including medical imaging and drug delivery, is currently undergoing a dramatic expansion. Diverse effects of different type NPs relating to mammalian reproductive tissues have been demonstrated. Th e objective of this study was to explore the in vitro effects of polymeric nanoparticle poly(ethylene glycol)-blockpolylactide methyl ether (PEG-b-PLA NPs) on functional state and viability of ovarian granulosa cells (GCs), which play an important role in maintaining ovarian function and female fertility...
April 25, 2017: Endocrine Regulations
https://www.readbyqxmd.com/read/28598107/-the-antitumor-effects-of-fisetin-on-ovarian-cancer-in-vitro-and-in-vivo
#12
Yi-Bo Meng, Chao Xiao, Xin-Lian Chen, Peng Bai, Yuan Yao, He Wang, Xue Xiao
OBJECTIVES: We attempted to survey the inhibit effect of fisetin with human ovarian cancer cell line SKOV3 and the xenograft and the mechanism of the effect. METHODS: The ovarian cancer cell line SKOV3 treated by fisetin were observed directly under the transmission electronmicroscope (TEM);MTT assay was used to determine cell viability.Flow cytometry was used to analyze the apoptosis in ovarian cancer cell line SKOV3.In addition,we established an ovarian cancer athymicnude rat model...
November 2016: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28588729/grifolin-induces-apoptosis-and-promotes-cell-cycle-arrest-in-the-a2780-human-ovarian-cancer-cell-line-via-inactivation-of-the-erk1-2-and-akt-pathways
#13
Hong Yan, Xiaoxia Che, Qingtao Lv, Lili Zhang, Samina Dongol, Yilin Wang, Hengzi Sun, Jie Jiang
Grifolin, a secondary metabolic product isolated from the mushroom Albatrellus confluence, has been demonstrated to possess antitumor activities in a variety of malignant cells. However, the signaling pathways and the molecular mechanisms underlying the anticancer effects of the agent in human ovarian cancer remain to be elucidated. The aim of the present study was to examine the effect of grifolin treatment on the human ovarian cancer cell line, A2780. MTT and flow cytometry analysis were used to analyze the viability of A2780 cells following treatment with grifolin...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28588062/secondary-somatic-mutations-restoring-rad51c-and-rad51d-associated-with-acquired-resistance-to-the-parp-inhibitor-rucaparib-in-high-grade-ovarian-carcinoma
#14
Olga Kondrashova, Minh Nguyen, Kristy Shield-Artin, Anna V Tinker, Nelson N H Teng, Maria I Harrell, Michael J Kuiper, Gwo-Yaw Ho, Holly Barker, Maria Jasin, Rohit Prakash, Elizabeth M Kass, Meghan R Sullivan, Gregory J Brunette, Kara A Bernstein, Robert L Coleman, Anne Floquet, Michael Friedlander, Ganessan Kichenadasse, David M O'Malley, Amit M Oza, James X Sun, Liliane Robillard, Lara Maloney, David D L Bowtell, Heidi Giordano, Matthew J Wakefield, Scott H Kaufmann, Andrew D Simmons, Thomas C Harding, Mitch Raponi, Iain A McNeish, Elizabeth M Swisher, Kevin Lin, Clare L Scott
High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC...
June 6, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28546799/lectin-array-and-glycogene-expression-analyses-of-ovarian-cancer-cell-line-a2780-and-its-cisplatin-resistant-derivate-cell-line-a2780-cp
#15
Ran Zhao, Wenjun Qin, Ruihuan Qin, Jing Han, Can Li, Yisheng Wang, Congjian Xu
BACKGROUND: Ovarian cancer is one of the most lethal gynecological malignancies, in which platinum resistance is a common cause of its relapse and death. Glycosylation has been reported to be involved in drug resistance, and glycomic analyses of ovarian cancer may improve our understanding of the mechanisms underlying cancer cell drug resistance and provide potential biomarkers and therapeutic targets. METHODS: The serous ovarian cancer cell line A2780 and its platinum-resistant counterpart A2780-cp were used in this study...
2017: Clinical Proteomics
https://www.readbyqxmd.com/read/28546758/distinct-implications-of-different-brca-mutations-efficacy-of-cytotoxic-chemotherapy-parp-inhibition-and-clinical-outcome-in-ovarian-cancer
#16
REVIEW
Robert L Hollis, Michael Churchman, Charlie Gourley
Approximately a fifth of ovarian carcinoma (OC) is associated with inherited germline mutations, most commonly in the DNA repair genes BRCA1 or BRCA2 (BRCA). BRCA1- and BRCA2-associated OCs have historically been described as a single subgroup of OC that displays a distinct set of characteristics termed the "BRCAness" phenotype. The hallmarks of this phenotype are superior clinical outcome and hypersensitivity to platinum-based chemotherapy and poly-(ADP-ribose) polymerase (PARP) inhibitors. However, growing evidence suggests that BRCA1- and BRCA2-associated OCs display distinct characteristics, most notably in long-term patient survival...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28543772/parp-inhibitor-rucaparib-induces-changes-in-nad-levels-in-cells-and-liver-tissues-as-assessed-by-mrs
#17
Gilberto S Almeida, Carlo M Bawn, Martin Galler, Ian Wilson, Huw D Thomas, Suzanne Kyle, Nicola J Curtin, David R Newell, Ross J Maxwell
Poly(adenosine diphosphate ribose) polymerases (PARPs) are multifunctional proteins which play a role in many cellular processes. Namely, PARP1 and PARP2 have been shown to be involved in DNA repair, and therefore are valid targets in cancer treatment with PARP inhibitors, such as rucaparib, currently in clinical trials. Proton magnetic resonance spectroscopy ((1) H-MRS) was used to study the impact of rucaparib in vitro and ex vivo in liver tissue from mice, via quantitative analysis of nicotinamide adenosine diphosphate (NAD(+) ) spectra, to assess the potential of MRS as a biomarker of the PARP inhibitor response...
May 22, 2017: NMR in Biomedicine
https://www.readbyqxmd.com/read/28508305/recent-advances-in-targeting-dna-repair-pathways-for-the-treatment-of-ovarian-cancer-and-their-clinical-relevance
#18
REVIEW
Katsutoshi Oda, Michihiro Tanikawa, Kenbun Sone, Mayuyo Mori-Uchino, Yutaka Osuga, Tomoyuki Fujii
Poly (ADP-ribose) polymerase (PARP) inhibitors have attracted much attention as one of the major molecular-targeted therapeutics for inhibiting DNA damage response. The PARP inhibitor, olaparib, has been clinically applied for treating certain recurrent ovarian cancer patients with BRCA1/2 mutations in Europe and the United States. It was also designated on 24 March 2017 as an orphan drug in Japan for similar clinical indications. In this review, we discuss (i) the prevalence of BRCA1/2 mutations in ovarian cancer, (ii) clinical trials of PARP inhibitors in ovarian cancer, (iii) genetic counseling for hereditary breast and ovarian cancer patients, and (iv) non-BRCA genes that may be associated with homologous recombination deficiency...
May 15, 2017: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28491146/parp-inhibitors-in-ovarian-cancer-evidence-experience-and-clinical-potential
#19
REVIEW
Tarra Evans, Ursula Matulonis
Inhibitors of poly(ADP-ribose) polymerase (PARP) are considered one of the most active and exciting new therapies for the treatment of ovarian cancer. The anticancer activity of PARP inhibitors is based on the DNA repair vulnerability of many ovarian cancer cells, and multiple mechanisms of action of PARP inhibitors have been identified. As single agents, PARP inhibitors have demonstrated their greatest activity in ovarian cancer cells that harbor mutations in BRCA genes. Additionally, recent phase III studies have shown that single-agent PARP inhibitor activity extends beyond BRCA-related cancers and can benefit patients with ovarian cancers that do not have known BRCA mutations, especially when clinical characteristics such as platinum sensitivity and high-grade serous histology are present...
April 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28488580/germline-mutations-in-pancreatic-cancer-and-potential-new-therapeutic-options
#20
REVIEW
Rille Pihlak, Juan W Valle, Mairéad G McNamara
Due to short-lived treatment responses in unresectable disease, pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest cancers. There is availability of new information about germline and sporadic mutations in the deoxyribonucleic acid (DNA) damage repair pathway in PDAC in recent decades and the expectation is that novel targeted therapies will thus be developed. A variety of germline mutations (BRCA2, BRCA1, PALB2, CDKN2A, ATM, TP53 and mismatch repair genes MLH1, MSH2, MSH6) have been reported in these patients with the highest prevalence being BRCA1/2...
April 20, 2017: Oncotarget
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