Transcription profiling of rat hearts isolated perfused and exposed to doxorubicin
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
SUBMITTER: Michael Zaugg
PROVIDER: E-GEOD-12260 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:We used microarrays to detail transcriptional changes in the rat heart in response to doxorubicin, a chemotherapeutic drug known to induce cardiac disfunction/heart failure Keywords: treatment vs control
2008-12-31 | GSE12260 | GEO
Project description:To compare expression profiles in the cardiomyocytes with wild type top2b and those with top2b deletion after in vivo treatment of mice with doxorubicin or drug vehicle Doxorubicin is widely used in modern cancer treatments, despite the advent of targeted therapy. However, a dose-dependent cardiotoxicity often limits its clinical use. The prevailing theory hypothesizes that doxorubicin-induced cardiotoxicity is the result of reactive oxygen species (ROS) generation due to redox-cycling of doxorubicin. Here we showed that cardiomyocyte-specific deletion of Topoisomerase II beta (Top2b) markedly reduced DNA double-strand breaks, apoptosis, and functional damages in doxorubicin-treated hearts. To investigate transcriptomic changes after doxorubicin treatment in wild type mouse and mouse with cardiac specific deletion of Top2b, we examined the expression profiles in 4 groups of mice (3/group), ie. wildtype mice with or without doxorubicin treatment and mice with Top2b deletion in the cardiomyocytes with or without doxorubicin treatment. Mice were treated with doxorubicin (25mg/kg, i.p.) or PBS (drug vehicle) for 16 hr or 72 hr. The heart was removed and cardiomyocytes were isolated by using a Langendorff apparatus. After purification, total RNA was extracted from the cardiomyocytes, purified, and used for gene expression analysis. Compared with that in control cardiomyocytes or cardiomyocytes with Top2b deletion, doxorubicin caused a significant expression change in the genome of cardiomyocytes from the wildtype mice. Among the changes, multiple genes encoding mitochondrial structural protein and components of the respiratory chain complexes were down-regulated 72 hr after treatment while multiple genes in the p53 pathway were up-regulated 16 hr after treatment in the wildtype cardiomyocytes. Expression changes were examined in 2 groups of mice (wild type and conditional knockout of top2b in the cardiomyocytes) treated with doxorubicin or PBS for 16 or 72 hours
2012-10-28 | E-GEOD-40289 | biostudies-arrayexpress
Project description:We have used chromatin immune-precipitation with parallel sequencing (ChIP-Seq) technology to identify genome-wide H3K4me3 binding in human lymphoblastoid cell lines treated with a DNA-damaging chemotherapeutic reagent doxorubicin. ChIP-Seq analysis of H3K4me3 binding sites in human lymphoblastoid cells treated with Doxorubicin or vehicle
2014-11-14 | E-GEOD-51713 | biostudies-arrayexpress
Project description:We have used chromatin immune-precipitation with parallel sequencing (ChIP-Seq) technology to identify genome-wide p53 binding in human lymphoblastoid cell lines treated with a DNA-damaging chemotherapeutic reagent doxorubicin. ChIP-Seq analysis of p53 binding sites in human lymphoblastoid cells treated with Doxorubicin or vehicle
2013-10-23 | E-GEOD-46991 | biostudies-arrayexpress
Project description:The FDA approved drug Doxorubicin provokes copious irreversible cardiotoxicity and even increases the risk of heart failure. Considering the multiple and interacted molecular pathways in cancer, there is a big possibility that tumors are simultaneously sensitive to different drugs. This makes achievable to study the combinations of drug, having the virtues of less toxicity, higher efficacy and potentially antagonizing drug resistance in cancer therapy. In the present study, we addressed the synergistic effects of ginsenoside Rh2 on doxorubicin-treated breast cancer bearing mice. We showed that Rh2 significantly enhanced the antitumor effects of doxorubicin and greatly attenuated the cardiotoxicity. Transcriptomic changes can clearly distinguish the chemotherapeutic groups and non-treated control groups. Transcriptomic analysis domestrated that Rh2 protection involved in multiple vital pathways including cellular senescece, fibrosis remodeling, apoptosis and inflammation.
2021-10-30 | GSE186765 | GEO
Project description:Objective: To assess the role of aldoketoreductases and other doxorubicin pharmacokinetic or pharmacogenomic genes in doxorubicin cytotoxicity, resistance, DNA binding activity, and subcellular localization, Methods: We conducted a whole genome microarray study to identify differences in between doxorubicin-sensitive MCF-7cc cells and doxorubicin-resistant MCF-7Dox2-12 cells in terms of their expression of genes related to doxorubicin pharmacokinetics or pharmacodynamics. Targets were then validated by pharmacologic inhibition in conjunction with drug metabolite profiling, drug localization, drug cytotoxicity, and drug DNA binding studies. Results: 2063 differentially expressed transcripts were identified, including 17% and 43% of genes or gene families associated with doxorubicin pharmacokinetics or pharmacodynamics (p values of significance of 0.05 and <0.0001, respectively). The largest changes in the expression of genes associated with doxorubicin pharmacokinetics and pharmacodynamics were chiefly among the aldo-keto reductases (AKRs) Akr1c2, Akr1c3 and Akr1b10 which convert doxorubicin to doxorubicinol. We observed that doxorubicinol exhibits dramatically reduced drug toxicity, reduced drug DNA-binding activity, and altered drug subcellular localization to lysosomes. Pharmacologic inhibition of these AKRs in MCF-7Dox2-12 cells restored drug cytotoxicity, and drug localization to the nucleus. Conclusion: These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledgebases to identify highly relevant genes associated with doxorubicin resistance. The products of one or more of these genes could effectively be shown to alter the drug’s properties, while inhibiting them restored drug DNA binding, cytotoxicity, and subcellular localization. Doxorubicin resistant cell lines of breast MCF-7 cells were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with four labelling replicates of both forward and reverse labellings plus another set of 8 arrays with forward labelling. Sixteen arrays were used for this experiments. The co-cultured control cells MCF-7cc12 was generated by parallel selection process in the absence of drug.
2012-11-22 | E-GEOD-27254 | biostudies-arrayexpress
Project description:Long-term effects of doxorubicin, a chemotherapy agent, on S. cerevisiae cells were investigated. Yeast cells were grown in the absence and presence of 20 µM doxorubicin in fully controlled bioreactors, in triplicates.
2020-03-04 | E-MTAB-6634 | biostudies-arrayexpress
Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent in selectively killing tumor cells. However, TRAIL monotherapy is not especially successful due to the fact that many cancer cells are resistant to TRAIL. Chemotherapeutic agents, such as doxorubicin have been shown to act synergistically with TRAIL on cancer cells, but the exact mechanisms of actions are poorly understood. In this study we performed high-throughput siRNA screening and genome-wide gene expression profiling on doxorubicin treated U1690 cells to explore novel mechanisms underlying doxorubicin-TRAIL synergy. The screening and expression profiling results were integrated and dihydroorotate dehydrogenase (DHODH) was identified to be a potential candidate. DHODH is rate-limiting enzyme in the pyrimidine synthesis pathway, and its expression was downregulated by doxorubicin and silencing of DHODH sensitized U1690 cells to TRAIL. Inhibition of DHODH activity by brequinar dramatically increased the sensitivity of U1690 cells to TRAIL-induced apoptosis, and was accompanied by downregulation of cFLIPL and mitochondrial depolarization. However, the expressions of DR4 and 5 were not changed in response to brequinar treatment in contrast to doxorubicin. In addition, uridine, an end product of the pyrimidine synthesis pathway was able to rescue the sensitization effects initialized by both brequinar and doxorubicin. Furthermore, other cancer cell lines, LNCaP, MCF-7 and HT-29 were also shown to be sensitized to TRAIL by brequinar. Taken together, our findings have identified a novel drug, brequinar, to be potentially utilized in TRAIL combinatorial cancer therapy and highlighted for the first time the importance of DHODH and pyrimidine pathway in mediating TRAIL sensitization in cancer cells. Total RNA obtained from small cell lung cancer U1690 cells either treated with DMSO control or 1 M-BM-5M doxorubicin for 12 or 24h.
2013-06-01 | E-GEOD-42531 | biostudies-arrayexpress
Project description:Doxorubicin induces cardiomypathy in oncology patients. This study is aimed at identifying molecular mechanisms of doxorubicin cardiac toxicity in rats. Transcription profiling of heart tissue of rats treated with saline or doxorubicin 1, 2 or 3 mg/kg/week by iv once per week for 2, 4 or 6 weeks. Some animals were allowed to recovery from drug administration for 2 or 4 weeks. Note the recovery column refers to whether an animal was let without drug for some weeks before sacrifice.
2012-07-01 | E-MTAB-1168 | biostudies-arrayexpress
Project description:The aim of this study is the characterize and compare heart and PBMC transcriptomes of rats treated with doxorubicin in order to isolate a list of similarly differentially regulated genes with an ultimate goal to indentify PBMC biomarkers for early prediction of doxirubicinduced cardiotoxicity Total RNA was isolated from PBMC and hearts of rats treated with doxirubicin or saline for 48 hrs and used for gene expression
2013-12-31 | E-GEOD-37260 | biostudies-arrayexpress