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Transcriptomic analysis of folic acid effects in doxorubicin-induced cardiotoxicity

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE64476 | GEO | 2015/11/12

SECONDARY ACCESSION(S): PRJNA271088

REPOSITORIES: GEO

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Transcriptomic analysis of folic acid effects in doxorubicin-induced cardiotoxicity

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

A safety screening platform for individualized cardiotoxicity assessment

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

Nicotinamide Mononucleotide administration prevents doxorubicin-induced cardiotoxicity and loss in physical activity in mice.

Project description:In this study we investigated whether nicotinamide mononucleotide (NMN) could protect against Doxorubicin-induced cardiotoxicity and physical dysfunction in vivo. To assess the short- and long-term toxicity, two Doxo regimens were tested, acute and chronic. In the acute study, C57BL6/J (B6) mice were injected intraperitoneally (i.p.) once with Doxo (20 mg/kg) and NMN (180 mg/kg/day, i.p.) was administered daily for five days before and after the Doxo injection. In the chronic study, B6 mice received a cumulative dose of 20 mg/kg Doxo administered in fractionated doses for five days. NMN (500 mg/kg/day) was supplied in the mice’s drinking water beginning five days before the first injection of Doxo and continuing for 60 days after.

2023-01-11 | GSE221003 | GEO

Separating DNA from chromatin damage activities detoxifies the anti-cancer drug doxorubicin

Project description:The anthracycline doxorubicin (Doxo) is one of the most effective and commonly used anti-cancer drugs. However, its clinical application is limited by severe side effects, such as cardiotoxicity, therapy-related tumors and infertility. Doxo induces both DNA damage through double-strand breaks and chromatin damage through histone eviction. We examined whether separating these activities would detoxify Doxo, while maintaining its chemotherapeutic efficacy. Here we present anthracycline variants harboring the histone eviction activity alone which remain potent anti-cancer drugs, while greatly alleviating cardiotoxicity and therapy-related tumor formation. This suggests that the treatment-limited side effects of Doxo in mice can be strongly reduced by modifying the chemical structure. The modified anthracycline anti-cancer drugs may provide effective chemotherapeutics allowing prolonged treatment and a higher quality of life post-treatment.

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Transcriptional analysis of doxorubicin-induced cardiotoxicity

Project description:Doxorubicin (Dox) is an effective chemotherapeutic agent against a broad range of tumors. However, a threshold dose of doxorubicin causes an unacceptably high incidence of heart failure and limits its clinical utility. We have established two models of doxorubicin cardiotoxicity in mice: 1) in an acute model, mice are treated with 15mg/kg of doxorubicin once; 2) in a chronic model, they receive 3mg/kg weekly for the first 12 of a total of 18 weeks. Using echocardiography, we have monitored left ventricular function of the mouse hearts during treatment in chronic model and seen the expected development of dilated cardiomyopathy (DCM). Treated mice showed histological abnormalities similar to those seen in patients with doxorubicin cardiomyopathy. To investigate transcriptional regulation in these models, we used a microarray we generated with over 5000 independent cDNA clones from murine heart and skeletal muscle. We have identified genes that respond to doxorubicin exposure in both model systems, and confirmed these results using real-time PCR. In the acute model, a set of genes is regulated early and rapidly returns to baseline levels, consistent with the half-life of doxorubicin. In the chronic model, which mimics the clinical situation much more closely, we identified dysregulated genes that implicate specific mechanisms of cardiac toxicity and may serve as biomarkers of doxorubicin induced dilated cardiomyopathy. Keywords: time course

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Human Induced Pluripotent Stem Cells Recapitulate Breast Cancer Patients’ Predilection to Doxorubicin-Induced Cardiotoxicity

Project description:Doxorubicin (Adriamycin) is an anthracycline chemotherapy agent effective in treating a wide range of malignancies1 with a well-established dose-response cardiotoxic side-effect that can lead to heart failure2-4. Even at relatively low cumulative doses of 200–250 mg/m2, the risk of cardiotoxicity is estimated at 7.8% to 8.8%4,5. Doxorubicin-induced cardiotoxicity (DIC) can range from asymptomatic reductions in left ventricular ejection fraction (LVEF) to highly symptomatic heart failure6,7. At present, it is not possible to predict which patients will be affected by DIC or adequately protect patients who are at risk for suffering this devastating side-effect8. Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate individual patients’ predilection to DIC at the single cell level. hiPSC-CMs derived from breast cancer patients who suffered clinical DIC are consistently more sensitive to doxorubicin toxicity, demonstrating decreased cell viability, mitochondrial/metabolic function, calcium handling, and antioxidant pathway gene expression, along with increased reactive oxygen species (ROS) production compared to hiPSC-CMs from patients who did not experience DIC. Together, our data indicate that hiPSC-CMs are a suitable platform for identifying and verifying the genetic basis and molecular mechanisms of DIC.

2016-04-18 | GSE76314 | GEO

Effects of VEGF-B on doxorubicin-induced cardiotoxicity

Project description:Doxorubicin is a widely used and effective anthracycline chemotherapy drug, which use is limited due to its cardiotoxic side effects. We show that gene therapy with AAV-VEGF-B can inhibit the doxorubicin-induced cardiac atrophy and whole body cachexia.

2016-09-30 | GSE81448 | GEO

mRNA array profiling on human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin

Project description:Cardiomyocytes derived from human pluripotent stem cells were exposed to the cardiotoxic drug Doxorubicin in order to assess the utility of this cell system as a model for drug-induced cardiotoxicity. Cells are exposed to different concentrations of doxorubicin for up to 48 hours followed by a 12 days recovery period.

2017-12-19 | E-MTAB-6045 | biostudies-arrayexpress

MicroRNA array profiling on human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin

2017-10-28 | E-MTAB-6052 | biostudies-arrayexpress

Effect of doxorubicin and SPEDOX-6 on human iPSC-derived cardiac spheroids comprised of cardiomyocytes, endothelial cells, and fibroblasts.

Project description:The chemotherapeutic doxorubicin (DOX) detrimentally impacts the heart during cancer treatment. This necessitates development of non-cardiotoxic delivery systems that retain DOX anticancer efficacy. We utilized human induced pluripotent stem cell-derived multi-lineage cardiac spheroids (hiPSC-CSs) to compare the anticancer efficacy and reduced cardiotoxicity of single protein encapsulated doxorubicin (SPEDOX-6), to standard unformulated (UF) DOX using RNA-sequencing. The cardiac spheroids are comprised of hiPSC-derived cardiomyocytes (hiPSC-CMs), hiPSC-derived endothelial cells (ECs), and hiPSC-derived cardiac fibroblasts (CFs) at an 8:1:1 ratio.

2023-07-01 | GSE235470 | GEO

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