Identifying common pathways for doxorubicin and carfilzomib-induced cardiotoxicities: transcriptomic and epigenetic profiling
Abstract Cancer therapy-related cardiovascular toxicity (CTR-CVT) is now recognised as one of the leading causes of long-term morbidity and mortality in cancer patients. To date, potential overlapping cardiotoxicity mechanism(s) across different chemotherapeutic classes have not been elucidated. Dox...
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Nature Portfolio
2025-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-87442-5 |
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| author | Conagh Kelly Dylan J. Kiltschewskij Angeline J.W. Leong Tatt Jhong Haw Amanda J. Croft Lohis Balachandran Dongqing Chen Danielle R. Bond Heather J. Lee Murray J. Cairns Aaron L. Sverdlov Doan T. M. Ngo |
| author_facet | Conagh Kelly Dylan J. Kiltschewskij Angeline J.W. Leong Tatt Jhong Haw Amanda J. Croft Lohis Balachandran Dongqing Chen Danielle R. Bond Heather J. Lee Murray J. Cairns Aaron L. Sverdlov Doan T. M. Ngo |
| author_sort | Conagh Kelly |
| collection | DOAJ |
| description | Abstract Cancer therapy-related cardiovascular toxicity (CTR-CVT) is now recognised as one of the leading causes of long-term morbidity and mortality in cancer patients. To date, potential overlapping cardiotoxicity mechanism(s) across different chemotherapeutic classes have not been elucidated. Doxorubicin, an anthracycline, and Carfilzomib, a proteasome inhibitor, are both known to cause heart failure in some patients. Given this common cardiotoxic effect of these chemotherapies, we aimed to investigate differential and common mechanism(s) associated with Doxorubicin and Carfilzomib-induced cardiac dysfunction. Primary human cardiomyocyte-like cells (HCM-ls) were treated with 1 µM of either Doxorubicin or Carfilzomib for 72 h. Both Doxorubicin and Carfilzomib induced a significant reduction in HCM cell viability and cell damage. DNA methylation analysis performed using MethylationEPIC array showed distinct and common changes induced by Doxorubicin and Carfilzomib (10,270 or approximately 12.9% of the DMPs for either treatment overlapped). RNA-seq analyses identified 5,643 differentially expressed genes (DEGs) that were commonly dysregulated for both treatments. Pathway analysis revealed that the PI3K-Akt signalling pathway was the most significantly enriched pathway with common DEGs, shared between Doxorubicin and Carfilzomib. We identified that there are shared cardiotoxicity mechanisms for Doxorubicin and Carfilzomib pathways that can be potential therapeutic targets for treatments across 2 classes of anti-cancer agents. |
| format | Article |
| id | doaj-art-3645340b2c3546b7893f2aa37f9ac632 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-3645340b2c3546b7893f2aa37f9ac6322025-02-09T12:35:16ZengNature PortfolioScientific Reports2045-23222025-02-0115112210.1038/s41598-025-87442-5Identifying common pathways for doxorubicin and carfilzomib-induced cardiotoxicities: transcriptomic and epigenetic profilingConagh Kelly0Dylan J. Kiltschewskij1Angeline J.W. Leong2Tatt Jhong Haw3Amanda J. Croft4Lohis Balachandran5Dongqing Chen6Danielle R. Bond7Heather J. Lee8Murray J. Cairns9Aaron L. Sverdlov10Doan T. M. Ngo11School of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleHeart and Stroke Research Program, Hunter Medical Research InstituteHeart and Stroke Research Program, Hunter Medical Research InstituteHeart and Stroke Research Program, Hunter Medical Research InstituteHeart and Stroke Research Program, Hunter Medical Research InstituteSchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleHeart and Stroke Research Program, Hunter Medical Research InstituteSchool of Biomedical Sciences and Pharmacy, The University of NewcastleAbstract Cancer therapy-related cardiovascular toxicity (CTR-CVT) is now recognised as one of the leading causes of long-term morbidity and mortality in cancer patients. To date, potential overlapping cardiotoxicity mechanism(s) across different chemotherapeutic classes have not been elucidated. Doxorubicin, an anthracycline, and Carfilzomib, a proteasome inhibitor, are both known to cause heart failure in some patients. Given this common cardiotoxic effect of these chemotherapies, we aimed to investigate differential and common mechanism(s) associated with Doxorubicin and Carfilzomib-induced cardiac dysfunction. Primary human cardiomyocyte-like cells (HCM-ls) were treated with 1 µM of either Doxorubicin or Carfilzomib for 72 h. Both Doxorubicin and Carfilzomib induced a significant reduction in HCM cell viability and cell damage. DNA methylation analysis performed using MethylationEPIC array showed distinct and common changes induced by Doxorubicin and Carfilzomib (10,270 or approximately 12.9% of the DMPs for either treatment overlapped). RNA-seq analyses identified 5,643 differentially expressed genes (DEGs) that were commonly dysregulated for both treatments. Pathway analysis revealed that the PI3K-Akt signalling pathway was the most significantly enriched pathway with common DEGs, shared between Doxorubicin and Carfilzomib. We identified that there are shared cardiotoxicity mechanisms for Doxorubicin and Carfilzomib pathways that can be potential therapeutic targets for treatments across 2 classes of anti-cancer agents.https://doi.org/10.1038/s41598-025-87442-5 |
| spellingShingle | Conagh Kelly Dylan J. Kiltschewskij Angeline J.W. Leong Tatt Jhong Haw Amanda J. Croft Lohis Balachandran Dongqing Chen Danielle R. Bond Heather J. Lee Murray J. Cairns Aaron L. Sverdlov Doan T. M. Ngo Identifying common pathways for doxorubicin and carfilzomib-induced cardiotoxicities: transcriptomic and epigenetic profiling Scientific Reports |
| title | Identifying common pathways for doxorubicin and carfilzomib-induced cardiotoxicities: transcriptomic and epigenetic profiling |
| title_full | Identifying common pathways for doxorubicin and carfilzomib-induced cardiotoxicities: transcriptomic and epigenetic profiling |
| title_fullStr | Identifying common pathways for doxorubicin and carfilzomib-induced cardiotoxicities: transcriptomic and epigenetic profiling |
| title_full_unstemmed | Identifying common pathways for doxorubicin and carfilzomib-induced cardiotoxicities: transcriptomic and epigenetic profiling |
| title_short | Identifying common pathways for doxorubicin and carfilzomib-induced cardiotoxicities: transcriptomic and epigenetic profiling |
| title_sort | identifying common pathways for doxorubicin and carfilzomib induced cardiotoxicities transcriptomic and epigenetic profiling |
| url | https://doi.org/10.1038/s41598-025-87442-5 |
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