Understanding the Protective Role of Exosomes in Doxorubicin-Induced Cardiotoxicity

Zhang, Guoxia; Yang, Xinyu; Su, Xin; An, Na; Yang, Fan; Li, Xinye; Jiang, Yuchen; Xing, Yanwei

doi:10.1155/2022/2852251

Cited by 5 publications

(8 citation statements)

References 132 publications

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“…In addition, iPSC-MSC-EXOs exhibited superior cardioprotective effects in DIC. Recently, many studies have indicated that in addition to excessive reactive oxygen species generation, apoptosis and pyroptosis, cardiomyocyte senescence plays an essential role in regulating DIC [ 34 , 35 ]. DOX induced cardiomyocyte senescence via activation of p38 MAPK/Redd1/NF-κB, leading to heart dysfunction in mice [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence

Zheng,

Liang,

Liu

et al. 2024

J Nanobiotechnol

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Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-β-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence

Zheng,

Liang,

Liu

et al. 2024

J Nanobiotechnol

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“…SEVs have been used to deliver chemotherapeutic drugs such as paclitaxel (PTX) [ 556 , 557 , 558 ] or doxycycline (DOX) [ 559 , 560 , 561 ]. While loading DOX in SEVs reduces its cardiotoxicity [ 562 , 563 ], it also enhances its efficacy when compared to traditional administration [ 562 , 564 ]. Packaging DOX into SEVs increases its stability, thus allowing a better collection within the tumor [ 564 ] with more limited side toxicity [ 565 ].…”

Section: Sevs As Nanovectors To Drive Therapy In Bcmentioning

confidence: 99%

Extracellular Vesicles in Breast Cancer: From Biology and Function to Clinical Diagnosis and Therapeutic Management

Loric

Denis

Desbène

et al. 2023

IJMS

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Breast cancer (BC) is the first worldwide most frequent cancer in both sexes and the most commonly diagnosed in females. Although BC mortality has been thoroughly declining over the past decades, there are still considerable differences between women diagnosed with early BC and when metastatic BC is diagnosed. BC treatment choice is widely dependent on precise histological and molecular characterization. However, recurrence or distant metastasis still occurs even with the most recent efficient therapies. Thus, a better understanding of the different factors underlying tumor escape is mainly mandatory. Among the leading candidates is the continuous interplay between tumor cells and their microenvironment, where extracellular vesicles play a significant role. Among extracellular vesicles, smaller ones, also called exosomes, can carry biomolecules, such as lipids, proteins, and nucleic acids, and generate signal transmission through an intercellular transfer of their content. This mechanism allows tumor cells to recruit and modify the adjacent and systemic microenvironment to support further invasion and dissemination. By reciprocity, stromal cells can also use exosomes to profoundly modify tumor cell behavior. This review intends to cover the most recent literature on the role of extracellular vesicle production in normal and cancerous breast tissues. Specific attention is paid to the use of extracellular vesicles for early BC diagnosis, follow-up, and prognosis because exosomes are actually under the spotlight of researchers as a high-potential source of liquid biopsies. Extracellular vesicles in BC treatment as new targets for therapy or efficient nanovectors to drive drug delivery are also summarized.

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“…Doxorubicin (DOX) is one of the anticancer drugs in the anthracycline group and is widely used clinically 17,18 . However, patients treated with DOX are frequently reported to have dilated cardiomyopathy and congestive heart failure 19 with the rate of morbidity and mortality increasing over time 20 .…”

Section: Introductionmentioning

confidence: 99%

“…Doxorubicin (DOX) is one of the anticancer drugs in the anthracycline group and is widely used clinically. 17,18 However, patients treated with DOX are frequently reported to have dilated cardiomyopathy and congestive heart failure 19 with the rate of morbidity and mortality increasing over time. 20 According to the FDA, dexrazoxane is the only drug approved for DOX-induced cardiomyopathy; however, it increases secondary malignant neoplasms.…”

Section: Introductionmentioning

confidence: 99%

A combination of isoliquiritigenin with Artemisia argyi and Ohwia caudata water extracts attenuates oxidative stress, inflammation, and apoptosis by modulating Nrf2/Ho‐1 signaling pathways in SD rats with doxorubicin‐induced acute cardiotoxicity

Yuan Hsieh,

Islam,

Kuo

et al. 2023

Environmental Toxicology

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Ohwia caudata (Thunb.) H. Ohashi (Leguminosae) also called as “Evergreen shrub” and Artemisia argyi H.Lév. and Vaniot (Compositae) also named as “Chinese mugwort” those two‐leaf extracts frequently used as herbal medicine, especially in south east Asia and eastern Asia. Anthracyclines such as doxorubicin (DOX) are commonly used as effective chemotherapeutic drugs in anticancer therapy around the world. However, chemotherapy‐induced cardiotoxicity, dilated cardiomyopathy, and congestive heart failure are seen in patients who receive DOX therapy, with the mechanisms underlying DOX‐induced cardiac toxicity remaining unclear. Mitochondrial dysfunction, oxidative stress, inflammatory response, and cardiomyocytes have been shown to play crucial roles in DOX‐induced cardiotoxicity. Isoliquiritigenin (ISL, 10 mg/kg) is a bioactive flavonoid compound with protective effects against inflammation, neurodegeneration, cancer, and diabetes. Here, in this study, our aim is to find out the Artemisia argyi (AA) and Ohwia caudata (OC) leaf extract combination with Isoliquiritigenin in potentiating and complementing effect against chemo drug side effect to ameliorate cardiac damage and improve the cardiac function. In this study, we showed that a combination of low (AA 300 mg/kg; OC 100 mg/kg) and high‐dose(AA 600 mg/kg; OC 300 mg/kg) AA and OC water extract with ISL activated the cell survival‐related AKT/PI3K signaling pathway in DOX‐treated cardiac tissue leading to the upregulation of the antioxidant markers SOD, HO‐1, and Keap‐1 and regulated mitochondrial dysfunction through the Nrf2 signaling pathway. Moreover, the water extract of AA and OC with ISL inhibited the inflammatory response genes IL‐6 and IL‐1β, possibly through the NFκB/AKT/PI3K/p38α/NRLP3 signaling pathways. The water extract of AA and OC with ISL could be a potential herbal drug treatment for cardiac hypertrophy, inflammatory disease, and apoptosis, which can lead to sudden heart failure.

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Understanding the Protective Role of Exosomes in Doxorubicin-Induced Cardiotoxicity

Cited by 5 publications

References 132 publications

Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence

Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence

Extracellular Vesicles in Breast Cancer: From Biology and Function to Clinical Diagnosis and Therapeutic Management

A combination of isoliquiritigenin with Artemisia argyi and Ohwia caudata water extracts attenuates oxidative stress, inflammation, and apoptosis by modulating Nrf2/Ho‐1 signaling pathways in SD rats with doxorubicin‐induced acute cardiotoxicity

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