Effect of doxorubicin and SPEDOX-6 on human iPSC-derived cardiac spheroids comprised of cardiomyocytes, endothelial cells, and fibroblasts.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE235470 | GEO | 2023/07/01
REPOSITORIES: GEO
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Project description:Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies only offer modest protection. Using stem cell-derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified OCT3 (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin. Functional validation studies in mice revealed that targeting OCT3 can attenuate cardiac dysfunction without compromising the anticancer properties of doxorubicin. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity
2021-02-19 | GSE157904 | GEO
Project description:Effect of doxorubicin and SPEDOX-6 on human iPSC-derived cardiac spheroids comprised of cardiomyocytes, endothelial cells, and fibroblasts.
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Project description:A major limitation in the cancer treatment is the ability of cancer cells to become resistant to chemotherapeutic drugs, by multidrug establishment. Here, we evaluate the possibility to utilize MC70, either as ABC transporters inhibitor or as anticancer agent, in monotherapy or in combination with doxorubicin for cancer treatment. The study was carried out in MCF7/ADR and Caco-2, breast and colon cancer cells, respectively. Cell growth and apoptosis were measured by MTT assay and DNA laddering Elisa kit, respectively. Cell cycle perturbation and cellular targets modulation were analyzed by flow cytometry and western blotting, respectively. MC70 was analyzed for its interaction with ABC transporters, MDR-1, BCRP and MRP-1, and for its anticancer activity. In MCF7/ADR, MC70 slight inhibited cell proliferation and strongly enhanced doxorubicin effectiveness; conversely in Caco-2, it inhibited cell growth without affecting doxorubicin efficacy. In addition, it induced apoptosis, canceled in favor of necrosis when it was given in combination with high doses of the anthracycline. Moreover, MC70 inhibited cell migration probably through its residual activity as sigma-1 ligand. Among the hypothesized molecular and cellular mechanisms responsible for all these effects, modulations of cell cycle, of pAkt and of the three MAPKs phosphorylation were evidenced while activity at transcription level was excluded. MC70 can be considered as a potential new anticancer agent with the capability to enhance doxorubicin effectiveness and an interesting role in the treatment of chemotherapy resistant tumors. The study included the basic characterization of MC70 efficacy as inhibitor of MDR transporters, the investigation of its anticancer behavior and the exploration of the molecular and cellular mechanisms responsible for it
2010-12-22 | E-GEOD-26250 | biostudies-arrayexpress
Project description:The use of anthracycline antibiotics such as doxorubicin (DOX) has greatly improved the mortality and morbidity of cancer patients. However, the associated risk of cardiomyopathy has limited their clinical application. DOX-associated cardiotoxicity is irreversible and progresses to heart failure (HF). For this reason, a better understanding of the molecular mechanisms underlying these adverse cardiac effects is essential to develop improved regimes that include cardioprotective strategies. MicroRNAs (miRNAs) are short non-coding RNAs that are able to post-trascriptionally regulate gene expression. MiRNAs have been demonstrated to be involved in both cancer and cardiovascular disease. Therefore, we were interested in unveiling the potential role of miRNAs in chemotherapy-induced HF. We used a combination of three different models to recreate this cardiac toxicity (acute in vitro DOX treatment, DOX-induced HF in vivo and a myocardial infarction -MI- leading to failure model) to study the pattern of dysregulated miRNAs. Using RNA from all three conditions, miRNA microarray profiling was performed and a common miRNA signature was identified. Interestingly, these dysregulated miRNAs have been previously identified as involved in the failing heart. Our results suggest that DOX is able to alter the expression of miRNAs implicated in HF, in vitro as well as in vivo. The present study is a microRNA profiling of the damaged cardiac muscle (cardiomyocyte cell population), following either myocardial infarction (MI) induction or doxorubicin (DOX) treatment. Two DOX-treated models were included: ARC exposed to DOX in vitro and a validated DOX-induced heart failure model generated by repeated administration of DOX injections.
2013-01-29 | E-GEOD-36239 | biostudies-arrayexpress
Project description:ABSTRACT Background: Viral myocarditis is a life-threatening illness that may lead to heart failure or cardiac arrhythmias. This study examined whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could be used to model the pathogenic processes of coxsackievirus-induced viral myocarditis and to screen antiviral therapeutics for efficacy. Methods and Results: Human iPSC-CMs were infected with a luciferase-expressing mutant of the coxsackievirus B3 strain (CVB3-Luc). Brightfield microscopy, immunofluorescence, and calcium imaging were used to characterize virally infected hiPSC-CMs. Viral proliferation on hiPSC-CMs was subsequently quantified using bioluminescence imaging. For drug screening, select antiviral compounds including interferon beta 1 (IFNβ1), ribavirin, pyrrolidine dithiocarbamate (PDTC), and fluoxetine were tested for their capacity to abrogate CVB3-Luc proliferation in hiPSC-CMs in vitro. The ability of some of these compounds to reduce CVB3-Luc proliferation in hiPSC-CMs was consistent with the reported drug effects in previous studies. Finally, mechanistic analyses via gene expression profiling of hiPSC-CMs infected with CVB3-Luc revealed an activation of viral RNA and protein clearance pathways within these hiPSC-CMs after IFNβ1 treatment. Conclusions: This study demonstrates that hiPSC-CMs express the coxsackievirus and adenovirus receptor, are susceptible to coxsackievirus infection, and can be used to confirm antiviral drug efficacy. Our results suggest that the hiPSC-CM/CVB3-Luc assay is a sensitive platform that could be used to screen novel antiviral therapeutics for their effectiveness in a high-throughput fashion. For this experiment, human induced pluripotent stem cell derived cardiomyocytes were infected with coxsackievirus at multiplicity of infection (MOI) of 5 for 8 hours. Cells were treated with and without interferon beta 1 in order to determine if treatment activates antiviral response genes and/or viral clearance pathways. 4 total samples (2 for each condition) were analyzed
2014-05-19 | E-GEOD-57781 | biostudies-arrayexpress
Project description:MTC-DOX is Doxorubicin or DOX, a chemotherapy drug, that is adsorbed, or made to "stick", to magnetic beads (MTCs). MTCs are tiny, microscopic particles of iron and carbon. When DOX is added to MTCs, DOX attaches to the carbon part of the MTCs. MTC-DOX is directed to and deposited in the area of a tumor, where it is thought that it then "leaks" through the blood vessel walls. Once in the surrounding tissues, it is thought that Doxorubicin becomes "free from" the magnetic beads and will then be able to act against the tumor cells. The iron component of the particle has magnetic properties, making it possible to direct MTC-DOX to specific tumor sites in the liver by placing a magnet on the body surface. It is hoped that MTC-DOX used with the magnet may target the chemotherapy drug directly to liver tumors and provide a treatment to patients with cancers that have spread to the liver.
| 2007949 | ecrin-mdr-crc
Project description:Tyrosine kinase inhibitors (TKIs), despite efficacy as anti-cancer therapies, are associated with cardiovascular side effects ranging from induced arrhythmias to heart failure. We have utilized patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), generated from 11 healthy individuals and 2 patients receiving cancer treatment, to screen FDA-approved TKIs for cardiotoxicities by measuring alterations in cardiomyocyte viability, contractility, electrophysiology, calcium handling, and signaling. With these data, we generated a “cardiac safety index” to assess cardiotoxicities of existing TKIs. Many TKIs with a low cardiac safety index exhibit cardiotoxicity in patients. We also derived endothelial cells (hiPSC-ECs) and cardiac fibroblasts (hiPSC-CFs) to examine cell type-specific cardiotoxicities. Using high-throughput screening, we determined that VEGFR2/PDGFR-inhibiting TKIs caused cardiotoxicity in hiPSC-CMs, hiPSC-ECs, and hiPSC-CFs. Using phosphoprotein analysis, we determined that VEGFR2/PDGFR-inhibiting TKIs led to a compensatory increase in cardioprotective insulin and insulin-like growth factor (IGF) signaling in hiPSC-CMs. Activating cardioprotective signaling with exogenous insulin or IGF1 improved hiPSC-CM viability during co-treatment with cardiotoxic VEGFR2/PDGFR-inhibiting TKIs. Thus, hiPSC-CMs can be used to screen for cardiovascular toxicities associated with anti-cancer TKIs, correlating with clinical phenotypes. This approach provides unexpected insights, as illustrated by our finding that toxicity can be alleviated via cardioprotective insulin/IGF signaling.
2016-11-02 | GSE89410 | GEO
Project description:Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to functional cardiac decline and ultimately, congestive heart failure (HF). Impaired mitochondrial function and energetics are thought to be key factors driving progression into HF. We have previously shown in a rat model of chronic intravenous DOX-administration that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and oxidative metabolism, including fatty acid oxidation. We hypothesized that AMPK activation could restore mitochondrial number and function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. Consequently, we set out to assess whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this clinically relevant rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. This was associated with normalisation of substrate supply to the heart, as AICAR prevented DOX-induced dyslipidaemia. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number. In addition, we found that AICAR reduced the degree of myocardial atrophy, and RNAseq analysis showed that this was driven by normalisation of protein synthesis pathways, which are impaired in DOX-treated rat hearts. Taken together, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass.
2024-11-01 | GSE218397 | GEO
Project description:The anthracycline, doxorubicin (Dox), is widely used in oncology, but it may it may cause a cardiomyopathy which has dismal prognosis and cannot be effectively prevented. The secretome of multipotent human amniotic fluid-derived stem cells (hAFS) has previously been demonstrated to reduce ischemic cardiac damage. Here, it is shown that the hAFS conditioned medium (hAFS-CM) antagonizes senescence and apoptosis of cardiomyocytes and cardiac progenitor cells, two major features of Dox cardiotoxicity. Mechanistic studies with primary mouse neonatal cardiomyocytes reveal that hAFS-CM inhibition of Dox-elicited senescence and apoptosis is paralleled by decreased DNA damage and is associated with nuclear translocation of NF-kB and upregulation of a set of genes controlled by NF-kB, namely Il6 and Cxcl1, which promote cardiomyocyte survival, and Cyp1b1 and Abcb1, which encode for proteins involved in Dox metabolism and efflux, respectively. The PI3K/Akt signaling cascade, upstream of NF-kB, is potently activated by the hAFS-CM and pre-treatment with a PI3K inhibitor abrogates NF-kB accumulation into the nucleus, modulation of its target genes, and prevention of Dox-initiated senescence and apoptosis in response to the hAFS-CM. This work may lay the ground for the development of a stem cell-based paracrine therapy of chemotherapy-related cardiotoxicity.
2016-10-30 | GSE74513 | GEO
Project description:Exposure to per- and polyfluoroalkyl substances (PFASs) such as perfluorooctanesulfonic acid (PFOS) has been associated with congenital heart disease (CHD) and decreased birth weight. PFAS exposure can disrupt signaling pathways relevant for cardiac development in stem cell derived cardiomyocyte assays, including PFOS-induced disruption to in vitro cardiac differentiation into contracting spheroids of cardiomyocytes; the PluriBeat assay. Notably, cell line origin can affect how the assay respond to PFAS exposure. Herein, we examine the effect of PFOS on cardiomyocyte differentiation by transcriptomics profiling of two different human induced pluripotent stem cell (hiPSC) lines, to see if they exhibit a common pattern of disruption. Two stages of differentiation, the cardiac progenitor stage (early) and the cardiomyocyte stage (late), were investigated.
2022-05-03 | GSE202077 | GEO