Gene expression associated with acquired paclitaxel resistance in ovarian cancer cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE172016 | GEO | 2021/07/02
REPOSITORIES: GEO
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Project description:The microtubule-stabilising drug paclitaxel has activity in relapsed ovarian cancer. However, resistance frequently develops. Oncolytic adenoviruses are a novel cancer therapy, and replicate selectively within and lyse malignant cells, leading to productive infection of neighbouring cells. We found increased efficacy of adenoviruses of multiple subtypes in paclitaxel-resistant ovarian cancer cells. There was increased expression of a key adenovirus receptor, CAR (coxsackie adenovirus receptor), due to increased transcription that resulted from histone modification. Moreover, CAR transcription increased in intraperitoneal xenografts with acquired paclitaxel resistance and in tumours from patients with paclitaxel-resistant ovarian cancer. Finally, we identified dysregulated cell cycle control as a second mechanism of increased adenovirus efficacy in paclitaxel-resistant ovarian cancer and that inhibition of CDK4/6 using PD-0332991 was able both to reverse paclitaxel resistance and reduce adenovirus efficacy. Thus, paclitaxel resistance increases oncolytic adenovirus efficacy via at least two separate mechanisms. Parental SKOV3 and paclitaxel-resistant SKOV3-TR cells were analysed in duplicate
2015-12-10 | E-GEOD-54772 | biostudies-arrayexpress
Project description:The microtubule-stabilising drug paclitaxel has activity in relapsed ovarian cancer. However, resistance frequently develops. Oncolytic adenoviruses are a novel cancer therapy, and replicate selectively within and lyse malignant cells, leading to productive infection of neighbouring cells. We found increased efficacy of adenoviruses of multiple subtypes in paclitaxel-resistant ovarian cancer cells. There was increased expression of a key adenovirus receptor, CAR (coxsackie adenovirus receptor), due to increased transcription that resulted from histone modification. Moreover, CAR transcription increased in intraperitoneal xenografts with acquired paclitaxel resistance and in tumours from patients with paclitaxel-resistant ovarian cancer. Finally, we identified dysregulated cell cycle control as a second mechanism of increased adenovirus efficacy in paclitaxel-resistant ovarian cancer and that inhibition of CDK4/6 using PD-0332991 was able both to reverse paclitaxel resistance and reduce adenovirus efficacy. Thus, paclitaxel resistance increases oncolytic adenovirus efficacy via at least two separate mechanisms.
2015-12-10 | GSE54772 | GEO
Project description:summary Ovarian cancer is the leading cause of death among gynecologic malignancies. This is partly due to a non-durable response to chemotherapy. Prediction of resistance to chemotherapy could be a key role in more personalized treatment. In the current study we aimed to examine if microRNA based predictors could predict resistance to chemotherapy in ovarian cancer, and to investigate if the predictors could be prognostic factors for progression free and overall survival. Methods Predictors of chemotherapy-resistance were developed based on correlation between miRNA expression and differences in measured growth inhibition in a variety of human cancer cell lines in the presence of Carboplatin, Paclitaxel and Docetaxel (deposited under accession number E-MTAB-327 in the ArrayExpress database of the European Bioinformatics Institute, 2012). These predictors were then, retrospectively, blindly validated in a cohort of 170 epithelial ovarian cancer patients treated with Carboplatin and Paclitaxel or Docetaxel as first line treatment. Results In a multivariate cox proportional analysis the predictors of chemotherapy-resistance were not able to predict time to progression after end of chemotherapy (hazard ratio: 0.64, 95% CI: 0.36 – 1.12, P=0.117). However, in a multivariate logistic analysis, where time to progression was considered as either more or less than 6 months, the predictors match clinical observed chemotherapy-resistance (odds ratio: 0.19, 95% CI: 0.05-0.73, P=0.015). Neither univariate nor multivariate, time-dependent, cox analysis for progression free survival (PFS) or overall survival (OS) in all 170 patients showed to match predicted resistance to chemotherapy (PFS: hazard ratio: 0.69, 95% CI: 0.40-1.19, P=0.183, OS: hazard ratio: 0.76, 95% CI: 0.42-1.40, P=0.386). Conclusion In the current study, microRNA based predictors of chemotherapy-resistance did not demonstrate any convincing correlation to clinical observed chemotherapy-resistance, progression free survival, or overall survival, in patients with epithelial ovarian cancer. However the predictors did reflect relapse more or less than 6 months.
2017-02-01 | GSE94320 | GEO
Project description:The taxanes, namely Paclitaxel and Docetaxel, are important and widely used cancer chemotherapy drugs in the treatment of invasive and metastatic human breast cancer. Although treatment with the taxanes is beneficial to many patients, drug-responsive tumors in patients with metastatic breast cancer often display resistance to these drugs, either initially or over time following the continued administration of chemotherapy drugs. To investigate the patterns of cross-resistance with the taxane drugs and to identify potential mechanisms of resistance, we generated a series of MDA-MB-231 taxane resistant cell lines. We then used microarrays to determine gene expression differences between sensitive, Docetaxel and Paclitaxel resistant MDA-MB-231 cells. RNA isolated from three independent passages of sensitive, Docetaxel and Paclitaxel resistant cell lines and purified using the Qiagen RNeasy Mini Kit. Total RNA was processed and hybridized to Affymetrix Genechip HU133A arrays.
2011-04-22 | E-GEOD-28784 | biostudies-arrayexpress
Project description:Purpose: Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Most of these patients are treated with platinum-based chemotherapies, but there is no biomarker model to guide their responses to these therapeutic agents. We have developed and independently tested our novel multivariate molecular predictors for forecasting patients' responses to individual drugs on a cohort of 58 ovarian cancer patients. Experimental Design: We adapted and applied the previously-published COXEN algorithm to develop molecular predictors for therapeutic responses of patients' tumors based on expression signatures derived from the NCI-60 in vitro drug activities and genomic expression data. Genome-wide candidate biomarkers were first triaged by examining expression patterns of frozen and formalin-fixed paraffin embedded (FFPE) tissue samples. We then identify initial drug sensitivity biomarkers for carboplatin and paclitaxel, respectively. These biomarkers were further narrowed by examining concordant expression patterns between cell lines and a historical set of ovarian cancer patients. Multivariate predictors were obtained from the NCI-60 cell lines and refined using historical patient cohorts. To independent validate these molecular predictors, we performed genome-wide profiling on FFPE samples of 58 ovarian cancer patients obtained prior to adjuvant chemotherapy. Results: Carboplatin predictor significantly stratified platinum sensitive and resistant patients (p = 0.019) with sensitivity = 93%, specificity = 33%, PPV = 65%, and NPV = 78%. Paclitaxel predictor also significantly stratified patients' responses (p = 0.033) with sensitivity = 96%, specificity = 26%, PPV = 61%, and NPV = 86%. The combination predictor for platinum-taxane combination demonstrated a significant survival difference between the predicted responders and nonresponders with median survival of 12.9 months vs. 8.1 months (p = 0.045). Conclusions: COXEN predictors successfully stratified platinum resistance and taxane response in this retrospective cohort, especially based on their FFPE tumor samples. Accurate prediction of chemotherapeutic response, especially to platinum agents is highly clinically relevant and could alter primary management of ovarian cancer. Gene expression data from 58 stage III-IV ovarian cancer patients treated with Carboplatin and Taxol agents
2012-08-21 | E-GEOD-30161 | biostudies-arrayexpress
Project description:The taxanes, namely Paclitaxel and Docetaxel, are important and widely used cancer chemotherapy drugs in the treatment of invasive and metastatic human breast cancer. Although treatment with the taxanes is beneficial to many patients, drug-responsive tumors in patients with metastatic breast cancer often display resistance to these drugs, either initially or over time following the continued administration of chemotherapy drugs. To investigate the patterns of cross-resistance with the taxane drugs and to identify potential mechanisms of resistance, we generated a series of MDA-MB-231 taxane resistant cell lines. We then used microarrays to determine gene expression differences between sensitive, Docetaxel and Paclitaxel resistant MDA-MB-231 cells.
2011-04-22 | GSE28784 | GEO
Project description:Tumor heterogeneity and resistance to chemotherapy represents a significant challenge in the clinical management of triple negative breast cancer (TNBC). By dissecting molecular pathways associated with treatment resistance, we sought to define patient sub-groups and define actionable targets for next-line treatment. Bulk RNA sequencing were performed on isogenic patient-derived xenografts (PDX) representing paclitaxel-sensitive and -resistant tumors. Pathways identified as upregulated in the resistant model were further explored as targets in downstream approcaches, and their clinical relevance evaluated in publicly available clincial data.
2024-10-01 | GSE265955 | GEO
Project description:Acquired drug resistance represents a major challenge in chemo-therapy treatment for various types of cancers. We have found that the retinoid X receptor–selective agonist bexarotene (LGD1069, Targretin) was efficacious in treating chemo-resistant cancer cells. The goal of this microarray study was to understand the mechanism of bexarotene’s role in overcoming acquired drug resistance using human breast cancer cells MDA-MB-231 as a model system and paclitaxel as model compound. After MDA-MB-231 cells were repeatedly treated with paclitaxel for 8 cycles with each cycle including a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium, MDA cells resistant to paclitaxel were developed and their growth was no longer inhibited by paclitaxel treatment. Those MDA cells with acquired drug resistance, when treated with paclitaxel and bexarotene in combination, could regain their sensitivity and their growth were again inhibited. Therefore, RNA samples from parental MDA-MB-231 cells, paclitaxel-resistant MDA cells treated with vehicle, paclitaxel alone or in combination with bexarotene, were used for perform global gene expression profiling with Affymetrix HG-U133A gene chips. Keywords: Drug Treatment
2011-07-19 | GSE12791 | GEO
Project description:Paclitaxel is a first-line drug for treating epithelial ovarian cancer (EOC). However, prognosis for patients with advanced stage cancer remains poor due to primary or acquired drug resistance. Therefore, overcoming chemoresistance is one of the greatest challenges in treating EOC. In this study, we identified microRNAs (miRNA) that regulate paclitaxel resistance and tested their potential utility as therapeutic targets. Paclitaxel-resistant cell lines were established using two EOC cell lines: SKVO3ip1 and HeyA8. miRNA PCR arrays showed that miR-194-5p was downregulated in paclitaxel-resistant cells. Forced expression of miR-194-5p resensitized resistant cells to paclitaxel. Conversely, miR-194-5p inhibition induced paclitaxel resistance in parental cells. In silico analysis and luciferase reporter assay revealed that MDM2 is a direct target of miR-194-5p. MDM2 was upregulated in paclitaxel resistant cells compared with parental cells. MDM2 inhibition also resensitized resistant cells to paclitaxel and forced MDM2 induced paclitaxel resistance in parental cells. miR-194-5p induced p21 upregulation and G1 phase arrest in resistant cells by downregulating MDM2. Furthermore, a public database showed that high MDM2 expression was associated with a shorter progression-free survival in EOC patients treated with paclitaxel. Collectively, our results show that restoring miR-194-5p expression resensitizes EOCs to paclitaxel, and this may be exploited as a therapeutic option.
2019-10-18 | GSE139043 | GEO
Project description:Acquired drug resistance represents a major challenge in chemo-therapy treatment for various types of cancers. We have found that the retinoid X receptorâselective agonist bexarotene (LGD1069, Targretin) was efficacious in treating chemo-resistant cancer cells. The goal of this microarray study was to understand the mechanism of bexaroteneâs role in overcoming acquired drug resistance using human breast cancer cells MDA-MB-231 as a model system and paclitaxel as model compound. After MDA-MB-231 cells were repeatedly treated with paclitaxel for 8 cycles with each cycle including a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium, MDA cells resistant to paclitaxel were developed and their growth was no longer inhibited by paclitaxel treatment. Those MDA cells with acquired drug resistance, when treated with paclitaxel and bexarotene in combination, could regain their sensitivity and their growth were again inhibited. Therefore, RNA samples from parental MDA-MB-231 cells, paclitaxel-resistant MDA cells treated with vehicle, paclitaxel alone or in combination with bexarotene, were used for perform global gene expression profiling with Affymetrix HG-U133A gene chips. Keywords: Drug Treatment MDA-MB-231 cells were exposed to regimens on a 10-day cycle: a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium. Paclitaxel resistant MDA-MB-231 cells (MDA-PR) were established within 8 cycles of such treatment (80 days). These MDA-PR cells were then treated with vehicle control, paclitaxel along, or the combination of 30 nM paclitaxel ( 3 days on and 7 days off) and 1 µM Targretin (10 days on) in a new 10-day cycle for 3 months. Thus, there are four treatment groups, parent MDA cells, MDA-PR, MDA-PR treated with paclitaxel, MDA-PR treated with paclitaxel and bexarotene, and each group had four biological replicates.
2011-07-18 | E-GEOD-12791 | biostudies-arrayexpress