Analysis of potential transcriptomic biomarkers for doxorubicin cardiotoxicity in peripheral blood
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
SUBMITTER: Valentina Todorova
PROVIDER: E-GEOD-37260 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
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
2013-12-31 | GSE37260 | GEO
Project description:The use of tubulin binders (TBs) in oncology indications often is associated with cardiotoxicity, the mechanism of which has not been elucidated. We observed that a single administration of TBs to rats caused an increase in the number of mitotic figures in the myocardial interstitium after 24 hours. We therefore hypothesized that interstitial cells are the primary target of TBs. To test this hypothesis, we evaluated the acute effects of a single intravenous administration of 3 reference TBs, colchicine (0.2 and 2 mg/kg), vinblastine (0.5 and 3 mg/kg), and vincristine (0.1 and 1 mg/kg) 6 and 24 hours after dosing. Mitotic arrest was identified at 24 hours in all high-dose groups based on an increase in the number of mitotic figures in the interstitium coupled with a dramatic decrease in the number of Ki67-positive interstitial cells. Analysis of the myocardial transcriptomic data further supported G2/M cell cycle arrest 6 hours after dosing with the high-dose groups of all 3 compounds. Apoptotic figures and an increase in the number of cleaved caspase 3-positive cells were identified at 6 and 24 hours at the highest dose of each compound almost exclusively in interstitial cells; a few cardiomyocytes were affected as well. Transcriptomic data further suggested that some of the affected interstitial cells were endothelial cells based on the up-regulation of genes typically associated with vascular damage and down-regulation of Endothelial Cell-Specific Molecule 1 and Apelin. Taken together, these data identify endothelial cells of the myocardium as the primary target of the cardiotoxicity of TBs and identify cell cycle arrest as the mechanism of this toxicity. Gene expression was profiled in the myocardium of rats at 6 and 24 hr after a single dose of colchicine, vinblastine or vincristine.
2010-01-01 | E-GEOD-19290 | biostudies-arrayexpress
Project description:Improvements in the diagnosis and treatment of cancer has revealed the long-term side effects of chemotherapeutics, particularly cardiotoxicity. Current clinical measures to track cardiotoxicity are insufficient to diagnose damage before it has been done, necessitating new, early biomarkers of cardiotoxicity. Here, we collected paired transcriptomics and metabolomics data characterizing in vitro cardiotoxicity to three compounds: 5-fluorouracil, acetaminophen, and doxorubicin. Standard gene enrichment and metabolomics approaches identify some commonly affected pathways and metabolites but are not able to readily identify mechanisms of cardiotoxicity. Here, we integrate this paired data with a genome-scale metabolic network reconstruction (GENRE) of the heart to identify shifted metabolic functions, unique metabolic reactions, and changes in flux in metabolic reactions in response to these compounds. Using this approach, we are able to confirm known mechanisms of doxorubicin-induced cardiotoxicity and provide hypotheses for mechanisms of cardiotoxicity for 5-fluorouracil and acetaminophen.
2021-06-01 | GSE166957 | GEO
Project description:Tyrosine Kinase Inhibitor Cardiotoxicity
| PRJNA352077 | ENA
Project description:Doxorubicin (DOXO), a chemotherapeutic drug, is cardiotoxic. We hypothesized that folic acid is an effective therapeutic agent in a mouse model of DOXO-induced cardiotoxicity. We performed genome-wide expression profiling to identify the underlying mechanisms. Male C57Bl6 2-mo old mice received DOXO (1x20 mg/kg, ip) or saline (sham). FA (10 mg/d) or placebo (plac) was administered 7d before DOXO administration until the end of the experiment (10d).
2015-11-12 | E-GEOD-64476 | biostudies-arrayexpress
Project description:Tyrosine kinase inhibitors (TKIs), as a class of small-molecule drugs that exert anti-tumor effects by inhibiting tyrosine kinase-catalyzed phosphorylation, have been used in the treatment of various cancers. Sorafenib, as a multi-targeted TKI drug, is the first-line treatment for advanced renal cell carcinoma and unresectable hepatocellular carcinoma. However, sorafenib has repeatedly been reported to cause cardiac events in patients without a history of heart diseases during clinical use, indicating that it has cardiotoxicity. Alternative splicing of cardiac contraction-related genes happens during heart development and cardiac diseases, and is critical for heart function. However, whether alternative splicing plays a role in drug-induced cardiotoxicity remains unexplored. RBM20 is an important cardiac-specific splicing factor, mutations of which cause dilated cardiomyopathy or other cardiac dysfunctions. Rbm20 also mediates alternative splicing of genes essential for heart contraction, which is often negatively affected in drug-induced cardiotoxicity. Existing studies do not fully explain the mechanism of sorafenib cardiotoxicity, and none of the relationship between cardiotoxicity of sorafenib and alternative splicing mediated by tissue-specific splicing factors, such as Rbm20, have been reported. In order to explore whether cardiac-specific alternative splicing plays a role in sorafenib-induced cardiotoxicity, we establish both cell and animal models of cardiotoxicity, and obtain the following results: (1) By constructing a rat animal model administered with sorafenib, we find that sorafenib causes abnormal cardiac function in rats, and the genes that undergo alternative splicing in rat hearts are related to cytoskeleton of actin; (2) Alternatively spliced genes induced by sorafenib in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are enriched in sarcomere, actin filament, calcium transient regulation, mitochondria, all of which are critical for cardiac contraction. These genes are associated with dilated cardiomyopathy, hypertrophic cardiomyopathy and other cardiomyopathy; (3) Sorafenib induces a decrease in the expression of cardiac-specific splicing factor RBM20; (3) Many genes whose splicing are altered by sorafenib overlap with Rbm20 targets, indicating that sorafenib may affect alternative splicing through Rbm20; (4) Sorafenib induces pathogenic alternative splicing of FHOD3, which is a RBM20 target gene and participates in myocardial sarcomere formation. Sorafenib also affects alternative splicing of SLC25A3, which encodes a phosphate transporter on the mitochondrial inner membrane and regulates ATP synthesis; (5) Enhancing the expression of RBM20 rescues the cardiotoxicity of sorafenib by reducing apoptosis and increasing ATP levels, which is mediated by reversing the alternative splicing of FHOD3 and SLC25A3 induced by sorafenib. This paper uncovers that sorafenib reduces the expression of RBM20 to cause pathogenic alternative splicing of genes related to myocardial sarcomere and energy mechanism, resulting in abnormal myocardial function. Increasing the expression of RBM20 reverses the alternative splicing of FHOD3 and SLC25A3 associated with cardiac sarcomeres and mitochondria respectively, rescuing the cardiotoxicity of sorafenib.
2023-12-07 | GSE222642 | GEO
Project description:Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following treatment of cancer patients is treatment limiting. It is unclear which patients will develop heart failure following therapy. Human pluripotent stem cell (hPSC)-derived cardiomyocytes present an unlimited cell source and may offer individualized solutions to this problem. We developed a platform to predict molecular and functional aspects of cardiotoxicity. Our platform can discriminate between the different cardiotoxic mechanisms of existing and novel anthracyclines Doxorubicin (DOXO), Aclarubicin (ACLA) and Amrubicin (AMR). DOXO and ACLA unlike AMR substantially affected the transcriptome, mitochondrial membrane integrity, contractile force and transcription factor availability. Cardiomyocytes recovered fully within two or three weeks, corresponding to the intermittent clinical treatment regimen. Our system permits the study of hPSC-cardiomyocyte recovery and the effects of accumulated dose after multiple dosing, allowing individualized cardiotoxicity evaluation, which effects millions of cancer patients treated with anthracyclines annually.
2023-10-01 | GSE232331 | GEO
Project description:The use of tubulin binders (TBs) in oncology indications often is associated with cardiotoxicity, the mechanism of which has not been elucidated. We observed that a single administration of TBs to rats caused an increase in the number of mitotic figures in the myocardial interstitium after 24 hours. We therefore hypothesized that interstitial cells are the primary target of TBs. To test this hypothesis, we evaluated the acute effects of a single intravenous administration of 3 reference TBs, colchicine (0.2 and 2 mg/kg), vinblastine (0.5 and 3 mg/kg), and vincristine (0.1 and 1 mg/kg) 6 and 24 hours after dosing. Mitotic arrest was identified at 24 hours in all high-dose groups based on an increase in the number of mitotic figures in the interstitium coupled with a dramatic decrease in the number of Ki67-positive interstitial cells. Analysis of the myocardial transcriptomic data further supported G2/M cell cycle arrest 6 hours after dosing with the high-dose groups of all 3 compounds. Apoptotic figures and an increase in the number of cleaved caspase 3-positive cells were identified at 6 and 24 hours at the highest dose of each compound almost exclusively in interstitial cells; a few cardiomyocytes were affected as well. Transcriptomic data further suggested that some of the affected interstitial cells were endothelial cells based on the up-regulation of genes typically associated with vascular damage and down-regulation of Endothelial Cell-Specific Molecule 1 and Apelin. Taken together, these data identify endothelial cells of the myocardium as the primary target of the cardiotoxicity of TBs and identify cell cycle arrest as the mechanism of this toxicity.
2010-01-01 | GSE19290 | GEO
Project description:Phosphodiesterase 10A (PDE10A), by degrading cAMP/cGMP, play critical roles in cardiovascular biology/disease. Cardiotoxicity is a clinical complication of chemotherapy. We aim to determine the role of PDE10A in cancer growth and cardiotoxicity induced by doxorubicin (DOX), a chemotherapy drug. We found that PDE10A deficiency/inhibition alleviated DOX-induced cardiotoxicity in C57Bl/6J mice, including myocardial atrophy, apoptosis, and dysfunction. RNAseq study revealed several PDE10A-regulated signaling associated with DOX-induced cardiotoxicity. In cancer cells, PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX in various cancer-cell lines. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protected against DOX-induced cardiotoxicity. In isolated cardiomyocytes (CMs), PDE10A contributed to DOX-induced CM death via promoting mitochondrial dysfunction, and to CM atrophy via potentiating foxo3 signaling. Collectively, our study elucidates a novel role for PDE10A in cardiotoxicity and cancer growth in vitro and in vivo, and suggest that PDE10A inhibition may represent a novel strategy in cancer therapy.
2023-06-22 | GSE224157 | GEO
Project description:Kinase inhibitors (KIs) represent an important class of anti-cancer drugs. Although cardiotoxicity is a serious adverse event associated with several KIs, the reasons remain poorly understood and its prediction remains challenging. Here, we perform transcriptomic profiling of human heart-derived primary cardiomyocyte cell lines treated with a panel of 26 FDA-approved KIs and classify their effects on subcellular pathways and processes. Individual cardiotoxicity patient reports for these KIs, obtained from the FDA Adverse Event Reporting System, are used to compute relative risk scores. These are then combined with cell line-derived transcriptomic datasets through elastic net regression analysis to identify a gene signature that can predict risk of cardiotoxicity. We also identify relationships between cardiotoxicity risk and structural/binding profiles of individual KIs. We conclude that acute transcriptomic changes in cell-based assays combined with drug substructures are predictive of KI-induced cardiotoxicity risk, and that they can be informative for future drug discovery.
2020-05-13 | GSE146096 | GEO