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Methylation ovarian cancer platinum resistance

Tushar Tomar, Nicolette G Alkema, Leroy Schreuder, Gert Jan Meersma, Tim de Meyer, Wim van Criekinge, Harry G Klip, Heidi Fiegl, Els van Nieuwenhuysen, Ignace Vergote, Martin Widschwendter, Ed Schuuring, Ate G J van der Zee, Steven de Jong, G Bea A Wisman
BACKGROUND: Despite an early response to platinum-based chemotherapy in advanced stage high-grade serous ovarian cancer (HGSOC), the majority of patients will relapse with drug-resistant disease. Aberrant epigenetic alterations like DNA methylation are common in HGSOC. Differences in DNA methylation are associated with chemoresponse in these patients. The objective of this study was to identify and validate novel epigenetic markers of chemoresponse using genome-wide analysis of DNA methylation in extreme chemoresponsive HGSOC patients...
June 23, 2017: BMC Medicine
Riikka J Lund, Kaisa Huhtinen, Jussi Salmi, Juha Rantala, Elizabeth V Nguyen, Robert Moulder, David R Goodlett, Riitta Lahesmaa, Olli Carpén
High-grade serous ovarian cancer is the most common ovarian cancer type. Although the combination of surgery and platinum-taxane chemotherapy provide an effective treatment, drug resistance frequently occurs leading to poor outcome. In order to clarify the molecular mechanisms of drug resistance, the DNA methylation and transcriptomic changes, associated with the development of drug resistance in high-grade serous ovarian cancer, were examined from patient derived malignant ascites cells. In parallel with large-scale transcriptome changes, cisplatin resistance was associated with loss of hypermethylation at several CpG sites primarily localized in the intergenic regions of the genome...
May 4, 2017: Scientific Reports
Xi Han, Yuanyuan Zhou, Yuanyi You, Jiaojiao Lu, Lijie Wang, Huilian Hou, Jing Li, Wei Chen, Le Zhao, Xu Li
The development of chemo-resistance impairs the outcome of the first line platinum-based chemotherapies for ovarian cancer. Deregulation of DNA methylation/demethylation provides a critical mechanism for the occurrence of chemo-resistance. The ten-eleven translocation (TET) family of dioxygenases including TET1/2/3 plays an important part in DNA demethylation, but their roles in cisplatin resistance have not been elucidated. Using cisplatin-sensitive and cisplatin-resistant ovarian cancer cell models, we found that TET1 was significantly upregulated in cisplatin-resistant CP70 cells compared with that in cisplatin-sensitive A2780 cells...
April 2017: Cell Biology International
Pavel Štarha, Ján Vančo, Zdeněk Trávníček, Jan Hošek, Jarmila Klusáková, Zdeněk Dvořák
A series of platinum(II) diiodido complexes containing 7-azaindole derivatives, having the general formula cis-[PtI2(naza)2] (1-8), has been prepared and thoroughly characterized, including X-ray structure analysis of cis-[PtI2(2Me4Claza)2]∙DMF (8∙DMF; 2Me4Claza = 2-methyl-4-chloro-7-azaindole). Complexes showed high in vitro cytotoxicity against nine human cancer cell lines (IC50 ranging from 0.4 to 12.8 μM), including the cisplatin-resistant ovarian cancer cell line (A2780R; IC50 = 1.0-3.5 μM). The results of in vivo testing, using the L1210 lymphocytic leukaemia model, at the equimolar doses of Pt with cisplatin (2 mg/kg) confirmed the activity of complex 8 comparable to cisplatin...
2016: PloS One
Karolina Lapinska, Genevieve Housman, Shannon Byler, Sarah Heerboth, Amber Willbanks, Anuja Oza, Sibaji Sarkar
BACKGROUND: Ovarian cancer is difficult to treat due to absence of selective drugs and tendency of platinum drugs to promote resistance. Combination therapy using epigenetic drugs is predicted to be a beneficial alternative. MATERIALS AND METHODS: This study investigated the effects of combination therapies using two structurally different histone deacetylase (HDAC) inhibitors (HDACi), sodium butyrate and suberanilohydroxamic acid (SAHA), with the calpain inhibitor calpeptin on two characteristically different ovarian cancer cell lines, CAOV-3 and SKOV-3...
2016: Anticancer Research
Tushar Tomar, Steven de Jong, Nicolette G Alkema, Rieks L Hoekman, Gert Jan Meersma, Harry G Klip, Ate Gj van der Zee, G Bea A Wisman
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far...
October 20, 2016: Genome Medicine
Maria de Leon, Horacio Cardenas, Edyta Vieth, Robert Emerson, Matthew Segar, Yunlong Liu, Kenneth Nephew, Daniela Matei
OBJECTIVES: Epigenetic alterations have been implicated in the development of platinum resistance in ovarian cancer (OC). In this study, we aimed to identify DNA methylation changes in platinum resistant tumors and their functional implications. METHODS: To identify DNA methylation alterations we used the Illumina 450k DNA methylation array and profiled platinum sensitive and resistant OC xenografts. Validation analyses employed RT-PCR and immunohistochemistry (IHC)...
September 2016: Gynecologic Oncology
Zachary B Jenner, Anil K Sood, Robert L Coleman
Rucaparib camsylate (CO-338; 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt) is a PARP1, 2 and 3 inhibitor. Phase I studies identified a recommended Phase II dose of 600 mg orally twice daily. ARIEL2 Part 1 established a tumor genomic profiling test for homologous recombination loss of heterozygosity quantification using a next-generation sequencing companion diagnostic (CDx). Rucaparib received US FDA Breakthrough Therapy designation for treatment of platinum-sensitive BRCA-mutated advanced ovarian cancer patients who received greater than two lines of platinum-based therapy...
June 2016: Future Oncology
Na Guo, Zhilan Peng, Jiawen Zhang
BACKGROUND: Platinum-based combination chemotherapy after surgery is considered a standard treatment; therefore, any recent drug development should be new, effective, and low toxic, and should have a synergistic effect with platinum. This study aimed to observe the growth of SKOV3 cells after treatment with cisplatin by combining with carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132) and to investigate the effect of the relationship between MG132 and cisplatin combination. MATERIALS AND METHODS: Cell growth was detected by methyl thiazolyl tetrazolium assay after treatment with MG132 at 0...
June 2016: International Journal of Gynecological Cancer
Nair A Bonito, Jane Borley, Charlotte S Wilhelm-Benartzi, Sadaf Ghaem-Maghami, Robert Brown
PURPOSE: Although high-grade serous ovarian cancer (HGSOC) is frequently chemoresponsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival (PFS) of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity...
June 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Vanesa Nogales, William C Reinhold, Sudhir Varma, Anna Martinez-Cardus, Catia Moutinho, Sebastian Moran, Holger Heyn, Ana Sebio, Agusti Barnadas, Yves Pommier, Manel Esteller
Platinum-derived drugs such as cisplatin and carboplatin are among the most commonly used cancer chemotherapy drugs, but very few specific molecular and cellular markers predicting differential sensitivity to these agents in a given tumor type have been clearly identified. Epigenetic gene silencing is increasingly being recognized as a factor conferring distinct tumoral drug sensitivity, so we have used a comprehensive DNA methylation microarray platform to interrogate the widely characterized NCI60 panel of human cancer cell lines with respect to CpG methylation status and cisplatin/carboplatin sensitivity...
January 19, 2016: Oncotarget
Michaela L Granados, Laurie G Hudson, Sabrina L Samudio-Ruiz
Acquisition of platinum resistance following first line platinum/taxane therapy is commonly observed in ovarian cancer patients and prevents clinical effectiveness. There are few options to prevent platinum resistance; however, demethylating agents have been shown to resensitize patients to platinum therapy thereby demonstrating that DNA methylation is a critical contributor to the development of platinum resistance. We previously reported the Epidermal Growth Factor Receptor (EGFR) is a novel regulator of DNA methyltransferase (DNMT) activity and DNA methylation...
2015: PloS One
Ping Chen, Kaisa Huhtinen, Katja Kaipio, Piia Mikkonen, Viljami Aittomäki, Rony Lindell, Johanna Hynninen, Annika Auranen, Seija Grénman, Rainer Lehtonen, Olli Carpén, Sampsa Hautaniemi
Disseminated high-grade serous ovarian cancer (HGS-OvCa) is an aggressive disease treated with platinum and taxane combination therapy. While initial response can be favorable, the disease typically relapses and becomes resistant to treatment. As genomic alterations in HGS-OvCa are heterogeneous, identification of clinically meaningful molecular markers for outcome prediction is challenging. We developed a novel computational approach (PSFinder) that fuses transcriptomics and clinical data to identify HGS-OvCa prognostic subgroups for targeted treatment...
August 1, 2015: Cancer Research
Ann-Marie Patch, Elizabeth L Christie, Dariush Etemadmoghadam, Dale W Garsed, Joshy George, Sian Fereday, Katia Nones, Prue Cowin, Kathryn Alsop, Peter J Bailey, Karin S Kassahn, Felicity Newell, Michael C J Quinn, Stephen Kazakoff, Kelly Quek, Charlotte Wilhelm-Benartzi, Ed Curry, Huei San Leong, Anne Hamilton, Linda Mileshkin, George Au-Yeung, Catherine Kennedy, Jillian Hung, Yoke-Eng Chiew, Paul Harnett, Michael Friedlander, Michael Quinn, Jan Pyman, Stephen Cordner, Patricia O'Brien, Jodie Leditschke, Greg Young, Kate Strachan, Paul Waring, Walid Azar, Chris Mitchell, Nadia Traficante, Joy Hendley, Heather Thorne, Mark Shackleton, David K Miller, Gisela Mir Arnau, Richard W Tothill, Timothy P Holloway, Timothy Semple, Ivon Harliwong, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Senel Idrisoglu, Timothy J C Bruxner, Angelika N Christ, Barsha Poudel, Oliver Holmes, Matthew Anderson, Conrad Leonard, Andrew Lonie, Nathan Hall, Scott Wood, Darrin F Taylor, Qinying Xu, J Lynn Fink, Nick Waddell, Ronny Drapkin, Euan Stronach, Hani Gabra, Robert Brown, Andrea Jewell, Shivashankar H Nagaraj, Emma Markham, Peter J Wilson, Jason Ellul, Orla McNally, Maria A Doyle, Ravikiran Vedururu, Collin Stewart, Ernst Lengyel, John V Pearson, Nicola Waddell, Anna deFazio, Sean M Grimmond, David D L Bowtell
Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance...
May 28, 2015: Nature
Nicholas W Bateman, Elizabeth Jaworski, Wei Ao, Guisong Wang, Tracy Litzi, Elizabeth Dubil, Charlotte Marcus, Kelly A Conrads, Pang-ning Teng, Brian L Hood, Neil T Phippen, Lisa A Vasicek, William P McGuire, Keren Paz, David Sidransky, Chad A Hamilton, G Larry Maxwell, Kathleen M Darcy, Thomas P Conrads
A majority of high-grade (HG) serous ovarian cancer (SOC) patients develop resistant disease despite high initial response rates to platinum/paclitaxel-based chemotherapy. We identified shed/secreted proteins in preclinical models of paclitaxel-resistant human HGSOC models and correlated these candidate proteins with patient outcomes using public data from HGSOC patients. Proteomic analyses of a HGSOC cell line secretome was compared to those from a syngeneic paclitaxel-resistant variant and from a line established from an intrinsically chemorefractory HGSOC patient...
April 3, 2015: Journal of Proteome Research
Steven Busschots, Sharon O'Toole, John J O'Leary, Britta Stordal
A major risk factor for ovarian cancer is germline mutations of BRCA1/2. It has been found that (80%) of cellular models with acquired platinum or taxane resistance display an inverse resistance relationship, that is collateral sensitivity to the other agent. We used a clinically relevant comparative selection strategy to develop novel chemoresistant cell lines which aim to investigate the mechanisms of resistance that arise from different exposures of carboplatin and taxol on cells having BRCA1 function (UPN251) or dysfunction (OVCAR8)...
August 1, 2015: Experimental Cell Research
Gaofeng Fan, Kazimierz O Wrzeszczynski, Cexiong Fu, Gang Su, Darryl J Pappin, Robert Lucito, Nicholas K Tonks
Although DNA encodes the molecular instructions that underlie the control of cell function, it is the proteins that are primarily responsible for implementing those instructions. Therefore quantitative analyses of the proteome would be expected to yield insights into important candidates for the detection and treatment of disease. We present an iTRAQ (isobaric tag for relative and absolute quantification)-based proteomic analysis of ten ovarian cancer cell lines and two normal ovarian surface epithelial cell lines...
February 1, 2015: Biochemical Journal
Lijun Shi, Hongjing Yu, Wei Zhang, Li Li, Qi Wang
OBJECTIVE: To establish a platinum resistance nude mice model of epithelial ovarian cancer (EOC) and investigate its resistance to cisplatin (DDP) biological characteristics, so as to provide evidences for exploring chemoresistence mechanisms and screening for reversal targets in vivo micro-environment. METHODS: The resistance model was produced by repeating a crossover subcutaneous injection of human ovarian cancer SKOV3 cells labelled green fluorescent protein (GFP) and transplatation of tumor fragment into nude mice...
July 2014: Zhonghua Fu Chan Ke za Zhi
Fang Fang, Joanne Munck, Jessica Tang, Pietro Taverna, Yinu Wang, David F B Miller, Jay Pilrose, Gavin Choy, Mohammad Azab, Katherine S Pawelczak, Pamela VanderVere-Carozza, Michael Wagner, John Lyons, Daniela Matei, John J Turchi, Kenneth P Nephew
PURPOSE: To investigate SGI-110 as a "chemosensitizer" in ovarian cancer and to assess its effects on tumor suppressor genes (TSG) and chemoresponsiveness-associated genes silenced by DNA methylation in ovarian cancer. EXPERIMENTAL DESIGN: Several ovarian cancer cell lines were used for in vitro and in vivo platinum resensitization studies. Changes in DNA methylation and expression levels of TSG and other cancer-related genes in response to SGI-110 were measured by pyrosequencing and RT-PCR...
December 15, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Dan Xie, Ru-Tie Yin, Ke-Ming Li, Ping Xiao, Long-Xia Tong
OBJECTIVE: To investigate the effects and mechanisms of hyperthermia combined with various platinum-based drugs cis-platinum (DDP), carboplatin (CBP), oxaliplatin (OXA) on the proliferation and apoptosis of ovarian cancer cell lines SKOV3. METHODS: SKOV3 cells were treated with different concentrations of anticancer drugs DDP (final concentration respectively 0, 1.25, 2.5, 5.0, 10.0, 20.0 microg/mL), CBP and OXA (both final concentration respectively 0, 2.5, 5.0, 10...
July 2014: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
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