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Phosphodiesterase 10A inactivation protects against doxorubicin-induced cardiotoxicity and concomitantly inhibits tumor growth

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE224157 | GEO | 2023/06/22

REPOSITORIES: GEO

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The human amniotic fluid stem cell secretome counteracts doxorubicin-induced cardiotoxicity

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

Effect of nicotinamide mononucleotide on doxorubicin-induced cardiac injury in mice

Project description:Doxorubicin (DOX) is the cornerstone of chemotherapy regimens for many malignancies, but its clinical usage is limited by severe cardiotoxicity. Accumulating evidence suggest that nicotinamide adenine dinucleotide (NAD+) depletion contributes to DOX-induced cardiotoxicity, making NAD+ boosting an appealing strategy. Nicotinamide mononucleotide (NMN) is an NAD+ precursor that shows promising therapeutic effects in various diseases. To understand the impact of NMN on gene expression in myocardial tissue of DOX-exposed mice, a RNA-seq assay was carried out.

2023-06-03 | GSE233644 | GEO

Epigenome analysis of doxorubicin-induced cardiotoxicity before and after treatemt of breast cancer patients

Project description:This study aimed to determine whether methylation signature of peripheral blood mononuclear cells (PBMCs) prior to the start of the first cycle of DOX-based chemotherapy could predict the risk of cardiotoxicity in breast cancer patients as well as determine if DOX treatment changed methlation profiles. The Illumina Infinium 450 Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 450k CpGs PBMCs samples before and after treatment. Samples included 10 samples from patients with normal ejection fraction after DOX treatment, 9 samples from patients with abnormal ejection fraction (indicative of cardiotoxicity) after DOX treatment.

2021-12-29 | GSE178887 | GEO

Project description:The treatment for DOX-induced cardiotoxicity

| PRJNA765675 | ENA

Imatinib-induced changes in expression profile of microRNA in plasma of mice - comparison with doxorubicin

Project description:Cardiotoxicity is serious adverse reaction of cancer chemotherapy and may lead to critical heart damage. Imatinib mesylate (IMB), a selective tyrosine kinase inhibitor, is sometimes accompanied by severe cardiovascular complications. To minimize the risk, early biomarkers of such complications are of utmost importance. MicroRNAs (miRNAs) are, nowadays intensively studied as potential biomarkers of many pathological processes. Many miRNAs appear to be specific in some tissues, including heart. Here, we have explored the potential of specific miRNAs to be early markers of IMB-induced cardiotoxicity. Doxorubicin (DOX), an anthracycline with well-known cardiotoxicity, was used for comparison. NMRI mice were treated with IMB or DOX for nine days in doses corresponding to the highest recommended doses in oncological patients. Then, plasmatic levels of miRNAs were analyzed by miRNA microarrays and selected cardio-specific miRNAs were quantified using qPCR. The plasmatic level of miR-1a, miR-133a, miR-133b, miR-339, miR-7058, miR-6236 and miR-6240 were the most different between IMB-treated and control mice. Interestingly, most of the miRNAs affected by DOX were also affected by IMB with the same trends. Concerning selected microRNAs in hearts of individual mice, only miR-34a was significantly increased after DOX treatment and only miR-205 was significantly decreased after IMB and DOX treatment. However, changes in any miRNA expression did not correlate with level of troponin T, classical marker of heart injury.

2020-01-01 | GSE121275 | GEO

The Secretome of Human Neonatal Mesenchymal Stem Cells Modulates Doxorubicin-induced Cytotoxicity: Impact in Non-tumour Cells

Project description:Breast cancer remains one of the leading causes of death in women, being the chemotherapeutic agent doxorubicin (Dox) among the most widely standard chemotherapy options for its treatment. However, its effective use has been severely limited owing to its well-documented cardiotoxic side effect that can lead to heart failure in a subset of patients. We have previously shown that a specific population of mesenchymal stem cells (MSCs) present immunomodulatory and regenerative properties, mainly granted by its secretome (CM), whose potential was improved when produced under 3D conditions. In cancer, the role of MSCs is still contradictory, with literature reporting both cancer promoting and suppressive effects. Therefore, we aimed at determining the effect of concomitant exposure of Dox with CM from 3D (CM3D) and 2D (CM2D) MSC cultures in breast cancer cells (MDA-MB-231) and in non-tumour breast epithelial cells (MCF10A) and differentiated AC16 cardiomyocytes. As such, the whole secretome was obtained by collecting and concentrating the culture media conditioned by MSCs in 2D (CM2D) and 3D (CM3D). A Ge-LC-MS/MS proteomic analysis revealed that CM3D effects may be linked to MSC cytoprotection and tumour development, namely through regulation of cell proliferation (CAPN1, CST1, LAMC2, RANBP3), migration (CCN3, MMP-8, PDCD5), invasion (TIMP-1/2), oxidative stress (AIFM1, CD9, GSR) and inflammation (ANXA5, CDH13, GDF-15). Overall, MSC-derived CM3D decreased Dox-induced cytotoxic effects on non-tumour breast cells and cardiomyocytes, without compromising Dox chemotherapeutic nature, highlighting the potential use of CM3D as an adjuvant in chemotherapy to reduce off-target side effects.

2022-02-17 | PXD029795 | Pride

The The Secretome of Human Neonatal Mesenchymal Stem Cells Modulates Doxorubicin-induced CytotoxicitySecretome of Human Neonatal Mesenchymal Stem Cells Modulates Doxorubicin-induced Cytotoxicity

2023-03-11 | PXD025633 | Pride

The effects of doxorubicin and blocking activin receptor 2B ligands in mice [muscle]

Project description:Doxorubicin is a widely used and effective anthracycline chemotherapy drug. However, it causes cardiotoxicity and also a few negative effects on skeletal muscle as well. As a result, cancer treatment might actually worsen cancer-induced cachexia and consequently the prognosis of the disease. Inhibiting myostatin/activin signaling is known to increase muscle size. This pathway blockade by soluble activin receptor IIB (sAcvR2B-Fc) has also prolonged survival in cancer, even of animals in which tumor growth is not inhibited. It is not known, however, whether blocking this pathway affects chemotherapy-induced muscle wasting. We found that doxorubicin induces muscle atrophy which is prevented by a blocker for activin receptor 2B ligands (sAcvR2B-Fc).

2016-09-25 | GSE77745 | GEO

The effects of doxorubicin and blocking activin receptor 2B ligands in mice [heart]

2017-12-04 | GSE97642 | GEO

MicroRNA profiling of the failing heart after myocardial infarction induction and doxorubicin treatment

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

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