Effect of doxorubicin on cardiac lipid metabolism-related transcriptome and the protective activity of Alda-1

Souza, Leonardo da Cunha Menezes; Fernandes, Fábio Henrique; Presti, Paula Torres; Ferreira, Aline Duarte; Salvadori, Daisy Maria Fávero

doi:10.1016/j.ejphar.2021.173955

Cited by 4 publications

(2 citation statements)

References 41 publications

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“…ALDH2, a mitochondrial matrix enzyme encoded in the nucleus, reduces the oxidative stress that acetaldehyde and its metabolites inflict on cells by degrading the metabolite 4‐HNE. In addition, doxorubicin causes aberrant accumulation of 4‐HNE‐modified protein adducts from lipid peroxidation, which has been linked to risk and may potentially influence the oxidative stress in the context of cardiotoxicity 17 , 18 . Our results have also shown that doxorubicin lowers ALDH2 protein and activity which drives β‐cell damage.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, doxorubicin exhibit abnormal accumulation of 4‐HNE‐modified protein adducts from lipid peroxidation, which has been confirmed to be a risk factor and potentially influences oxidative stress during cardiotoxicity. Remarkably, ALDH2 activation shows reduced 4‐HNE‐modified protein adducts and protein expression due to improved mitochondrial metabolism against doxorubicin induced cardiotoxicity 17 , 18 . However, the association between ALDH2 and doxorubicin induced oxidative stress in β‐cells has not been studied.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial ALDH2 improves ß‐cell survival and function against doxorubicin‐induced apoptosis by targeting CK2 signaling

Karunakaran,

Ha,

Elumalai

et al. 2024

J of Diabetes Invest

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AimsThe aim of this study was to better understand how the chemotherapy drug doxorubicin contributes to the development of β‐cell dysfunction and to explore its relationship with mitochondrial aldehyde dehydrogenase‐2 (ALDH2).Materials and MethodsIn order to investigate this hypothesis, doxorubicin was administered to INS‐1 cells, a rat insulinoma cell line, either with or without several target protein activators and inhibitors. ALDH2 activity was detected with a commercial kit and protein levels were determined with western blot. Mitochondrial ROS, membrane potential, and lipid ROS were determined by commercial fluorescent probes. The cell viability was measured by CCK‐assay.ResultsExposure of INS‐1 cells to doxorubicin decreased active insulin signaling resulting in elevated ALDH2 degradation, compared with control cells by the induction of acid sphingomyelinase mediated ceramide induction. Further, ceramide induction potentiated doxorubicin induced mitochondrial dysfunction. Treatment with the ALDH2 agonist, ALDA1, blocked doxorubicin‐induced acid sphingomyelinase activation which significantly blocked ceramide induction and mitochondrial dysfunction mediated cell death. Treatment with the ALDH2 agonist, ALDA1, stimulated casein kinase‐2 (CK2) mediated insulin signaling activation. CK2 silencing neutralized the function of ALDH2 in the doxorubicin treated INS‐1 cells.ConclusionsMitochondrial ALDH2 activation could inhibit the progression of doxorubicin induced pancreatic β‐cell dysfunction by inhibiting the acid sphingomyelinase induction of ceramide, by regulating the activation of CK2 signaling. Our research lays the foundation of ALDH2 activation as a therapeutic target for the precise treatment of chemotherapy drug induced β‐cell dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitochondrial ALDH2 improves ß‐cell survival and function against doxorubicin‐induced apoptosis by targeting CK2 signaling

Karunakaran,

Ha,

Elumalai

et al. 2024

J of Diabetes Invest

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Exploration of Key Immune-Related Transcriptomes Associated with Doxorubicin-Induced Cardiotoxicity in Patients with Breast Cancer

Xiong,

Yang,

et al. 2023

Cardiovasc Toxicol

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Based on a few studies, heart failure patients with breast cancer were assessed to find potential biomarkers for doxorubicin-induced cardiotoxicity. However, key immune-related transcriptional markers linked to doxorubicin-induced cardiotoxicity in breast cancer patients have not been thoroughly investigated. We used GSE40447, GSE76314, and TCGA BRCA cohorts to perform this study. Then, we performed various bioinformatics approaches to identify the key immune-related transcriptional markers and their association with doxorubicin-induced cardiotoxicity in patients with breast cancer. We found 255 upregulated genes and 286 downregulated genes in patients with doxorubicin-induced heart failure in breast cancer. We discovered that in patients with breast cancer comorbidity doxorubicin-induced cardiotoxicity, the 58 immunological genes are elevated (such as CPA3, VSIG4, GATA2, RFX2, IL3RA, and LRP1), and the 60 genes are significantly suppressed (such as MS4A1, FCRL1, CD200, FCRLA, FCRL2, and CD79A). Furthermore, we revealed that the immune-related differentially expressed genes (DEGs) are substantially associated with the enrichment of KEGG pathways, including B-cell receptor signaling pathway, primary immunodeficiency, chemokine signaling pathway, hematopoietic cell lineage, cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, MAPK signaling pathway, focal adhesion, dilated cardiomyopathy, cell adhesion molecule, etc. Moreover, we discovered that the doxorubicin-induced immune-related genes are crucially involved in the protein–protein interaction and gene clusters. The immune-related genes, including IFIT5, XCL1, SPIB, BTLA, MS4A1, CD19, TCL1A, CD83, CD200, FCRLA, CD79A, BIRC3, and IGF2R are significantly associated with a poor survival prognosis of breast cancer patients and showed diagnostic efficacy in patients with breast cancer and heart failure. Molecular docking revealed that the survival-associated genes interact with the doxorubicin with appreciable binding affinity. Finally, we validated the expression level of immune-related genes in breast cancer patients-derived cardiomyocytes with doxorubicin-induced cardiotoxicity and found that the level of RAD9A, HSPA1B, GATA2, IGF2R, CD200, ERCC8, and BCL11A genes are consistently dysregulated. Our findings offered a basis for understanding the mechanism and pathogenesis of the cardiotoxicity caused by doxorubicin in breast cancer patients and predicted the interaction of immune-related potential biomarkers with doxorubicin.

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CD146/MCAM links doxorubicin-induced epigenetic dysregulation to the impaired fatty acid transportation in H9c2 cardiomyoblasts

Hasan,

Obara,

Sato

et al. 2024

Biochemical and Biophysical Research Communications

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Effect of doxorubicin on cardiac lipid metabolism-related transcriptome and the protective activity of Alda-1

Cited by 4 publications

References 41 publications

Mitochondrial ALDH2 improves ß‐cell survival and function against doxorubicin‐induced apoptosis by targeting CK2 signaling

Mitochondrial ALDH2 improves ß‐cell survival and function against doxorubicin‐induced apoptosis by targeting CK2 signaling

Exploration of Key Immune-Related Transcriptomes Associated with Doxorubicin-Induced Cardiotoxicity in Patients with Breast Cancer

CD146/MCAM links doxorubicin-induced epigenetic dysregulation to the impaired fatty acid transportation in H9c2 cardiomyoblasts

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