Distinct genetic alterations occur in ovarian tumor cells selected for combined resistance to carboplatin and docetaxel

Abstract

BackgroundCurrent protocols for the treatment of ovarian cancer include combination chemotherapy with a platinating agent and a taxane. However, many patients experience relapse of their cancer and the development of drug resistance is not uncommon, making successful second line therapy difficult to achieve. The objective of this study was to develop and characterize a cell line resistant to both carboplatin and docetaxel (dual drug resistant ovarian cell line) and to compare this cell line to cells resistant to either carboplatin or docetaxel.MethodsThe A2780 epithelial endometrioid ovarian cancer cell line was used to select for isogenic carboplatin, docetaxel and dual drug resistant cell lines. A selection method of gradually increasing drug doses was implemented to avoid clonal selection. Resistance was confirmed using a clonogenic assay. Changes in gene expression associated with the development of drug resistance were determined by microarray analysis. Changes in the expression of selected genes were validated by Quantitative Real-Time Polymerase Chain Reaction (QPCR) and immunoblotting.ResultsThree isogenic cell lines were developed and resistance to each drug or the combination of drugs was confirmed. Development of resistance was accompanied by a reduced growth rate. The microarray and QPCR analyses showed that unique changes in gene expression occurred in the dual drug resistant cell line and that genes known to be involved in resistance could be identified in all cell lines.ConclusionsOvarian tumor cells can acquire resistance to both carboplatin and docetaxel when selected in the presence of both agents. Distinct changes in gene expression occur in the dual resistant cell line indicating that dual resistance is not a simple combination of the changes observed in cell lines exhibiting single agent resistance.

Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

“…Also, as neither UPN251-7C nor UPN251-7T had significant sensitivity to oxaliplatin while UPN251-6TALT did, this may indicate a novel mechanism of resistance being generated between this dual carboplatin/taxol resistant model and our singularly non-cross-resistant models. This evidence is supported by the finding of (Armstrong et al 2012) discussed above.…”

“…Another study developed a dual carboplatin and docetaxel resistant subline from A2780 ovarian cancer cells which are cross resistant to both agents as well as two singularly resistant sublines resistant to each agent but not cross resistant to the other. All of the sublines were selected for in parallel (Armstrong et al 2012). Gene profiling revealed that the dual model contains genetic changes not present in the singularly resistant models demonstrating that combined drug resistance may not be a simple combination of changes present in singleagent resistant cell lines but can contain novel changes.…”

Nanoceria-mediated delivery of doxorubicin enhances the anti-tumour efficiency in ovarian cancer cells via apoptosis

“…On the other hand, LGSC and MC is the least common among the major types of ovarian carcinomas. Therefore, we have used three different human ovarian cancer cell lines, A2780 (EC model) 47 , SKOV-3 (COC model) 48 , and CAOV-3 (HGSC model) 49 to check the in vitro anti-tumor activity of CeO 2 /DOX nanoparticles. The in vitro cytotoxicity and cell apoptosis experiments confirmed that CeO 2 /DOX exhibited higher tumour cell growth inhibition over free DOX in all of the tested human ovarian cancer cells.…”

STAT1‐associated intratumoural TH1 immunity predicts chemotherapy resistance in high‐grade serous ovarian cancer

“…A major hurdle in HGSC management is the development of resistance to chemotherapy via both intrinsic and acquired mechanisms . In the current study, we investigated elements within the IFN pathway that potentially mediate the STAT1 associated pre‐existing tumour immune state and determine eventual response to chemotherapy via recruiting effector cytotoxic CD8 + T cells in the chemotherapy naïve HGSC tumours.…”