MicroRNA in the Diagnosis and Treatment of Doxorubicin-Induced Cardiotoxicity

Kuang, Ziyu; Wu, Jingyuan; Tan, Ying; Zhu, Guanghui; Li, Jie; Wu, Min

doi:10.3390/biom13030568

Cited by 8 publications

(5 citation statements)

References 221 publications

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“…Dox is widely used in liver cancer chemotherapy treatment. However, DOX-induced cardiotoxicity greatly limits its clinical therapeutic utility ( 26 ). In the present study, it was examined whether CUIIa strengthened the anticancer effect of DOX and lowered cardiotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Cucurbitacin IIa promotes the immunogenic cell death‑inducing effect of doxorubicin and modulates immune microenvironment in liver cancer

Li,

Wang,

Zhang

et al. 2024

Int J Oncol

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The immunogenic cell death (ICD) has aroused great interest in cancer immunotherapy. Doxorubicin (DOX), which can induce ICD, is a widely used chemotherapeutic drug in liver cancer. However, DOX-induced ICD is not potent enough to initiate a satisfactory immune response. Cucurbitacin IIa (CUIIa), a tetracyclic triterpene, is a biologically active compound present in the Cucurbitaceae family. The present study assessed the effects of the combination of DOX and CUIIa on the viability, colony formation, apoptosis and cell cycle of HepG2 cells. In vivo anticancer effect was performed in mice bearing H22 tumor xenografts. The hallmark expression of ICD was tested using immunofluorescence and an ATP assay kit. The immune microenvironment was analyzed using flow cytometry. The combination of CUIIa and DOX displayed potent apoptosis inducing, cell cycle arresting and in vivo anticancer effects, along with attenuated cardiotoxicity in H22 mice. The combination of DOX and CUIIa also facilitated ICD as manifested by elevated high-mobility group box 1, calreticulin and ATP secretion. This combination provoked a stronger immune response in H22 mice, including dendritic cell activation, increment of cytotoxic T cells and T helper 1 cells. Moreover, the proportion of immunosuppressive cells including myeloid-derived suppressor cells, T regulatory cells and M2-polarized macrophages, decreased. These data suggested that CUIIa is a promising combination partner with DOX for liver cancer treatment, probably via triggering ICD and remolding the immune microenvironment.

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Section: Resultsmentioning

confidence: 99%

Cucurbitacin IIa promotes the immunogenic cell death‑inducing effect of doxorubicin and modulates immune microenvironment in liver cancer

Li,

Wang,

Zhang

et al. 2024

Int J Oncol

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“…The fact that miRNAs have strong and documented roles in the development of cardiovascular diseases ( Wang, 2010 ; Romaine et al, 2015 ; Barwari et al, 2016 ; Chen et al, 2017 ; Dhingra and Vasan, 2017 ; Peters et al, 2020 ; Laggerbauer and Engelhardt, 2022 ; Gargiulo et al, 2023 ) means that it is expected that miRNAs are involved in the complex pathogenesis of ANT-induced cardiotoxicity. Notably, ANT exposure has already been reported to cause differential expression in various miRNAs (reviewed in Ruggeri et al, 2018b ; Kawano and Adamcova, 2022 ; Yarmohammadi et al, 2023 ; Kuang et al, 2023 ; Chen and Xu, 2021 ; Li et al, 2022 ). Chaudhari et al (2016) described the early deregulation of miR-187-3p, miR-182-5p, miR-486-3p, miR-486-5p, miR-34a-3p, miR-4423-3p, miR-34c-3p, miR-34c-5p, and miR-1303 in iPSCs exposed in vitro to 156 nM doxorubicin (DOX), as well as the prolonged upregulation of miR-182-5p, miR-4423-3p, and miR-34c-5p.…”

Section: Discussionmentioning

confidence: 99%

Cardiac miRNA expression during the development of chronic anthracycline-induced cardiomyopathy using an experimental rabbit model

Adamcova,

Parova,

Lencova-Popelova

et al. 2024

Front. Pharmacol.

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Background: Anthracycline cardiotoxicity is a well-known complication of cancer treatment, and miRNAs have emerged as a key driver in the pathogenesis of cardiovascular diseases. This study aimed to investigate the expression of miRNAs in the myocardium in early and late stages of chronic anthracycline induced cardiotoxicity to determine whether this expression is associated with the severity of cardiac damage.Method: Cardiotoxicity was induced in rabbits via daunorubicin administration (daunorubicin, 3 mg/kg/week; for five and 10 weeks), while the control group received saline solution. Myocardial miRNA expression was first screened using TaqMan Advanced miRNA microfluidic card assays, after which 32 miRNAs were selected for targeted analysis using qRT-PCR.Results: The first subclinical signs of cardiotoxicity (significant increase in plasma cardiac troponin T) were observed after 5 weeks of daunorubicin treatment. At this time point, 10 miRNAs (including members of the miRNA-34 and 21 families) showed significant upregulation relative to the control group, with the most intense change observed for miRNA-1298-5p (29-fold change, p < 0.01). After 10 weeks of daunorubicin treatment, when a further rise in cTnT was accompanied by significant left ventricle systolic dysfunction, only miR-504-5p was significantly (p < 0.01) downregulated, whereas 10 miRNAs were significantly upregulated relative to the control group; at this time-point, the most intense change was observed for miR-34a-5p (76-fold change). Strong correlations were found between the expression of multiple miRNAs (including miR-34 and mir-21 family and miR-1298-5p) and quantitative indices of toxic damage in both the early and late phases of cardiotoxicity development. Furthermore, plasma levels of miR-34a-5p were strongly correlated with the myocardial expression of this miRNA.Conclusion: To the best of our knowledge, this is the first study that describes alterations in miRNA expression in the myocardium during the transition from subclinical, ANT-induced cardiotoxicity to an overt cardiotoxic phenotype; we also revealed how these changes in miRNA expression are strongly correlated with quantitative markers of cardiotoxicity.

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“…miRNAs function as essential mediators in homeostasis and pathological alterations of diseases [ 28 ]. Recently, many miRNAs have been found to induce abnormal functions of pulmonary artery smooth muscle cells and get involved in pulmonary vascular remodeling [ 29 – 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Here, we discovered that exosomal miR-663b from M1macrophage induces multifunction disorders of PASMCs through dampening the AMPK/Sirt1 pathway activation (Figure 9). miRNAs function as essential mediators in homeostasis and pathological alterations of diseases [28]. Recently, many miRNAs have been found to induce abnormal functions of pulmonary artery smooth muscle cells and get involved in pulmonary vascular remodeling [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

Exosomal miR-663b from “M1” macrophages promotes pulmonary artery vascular smooth muscle cell dysfunction through inhibiting the AMPK/Sirt1 axis

et al. 2023

Aging

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Background: Inflammatory mediators from macrophages are proven to be involved in pulmonary vascular remodeling in pulmonary hypertension (PH). Here, this study intends to explore the mechanism of “M1” macrophage-derived exosomal miR-663b in pulmonary artery smooth muscle cells (PASMCs) dysfunctions and pulmonary hypertension. Methods: Hypoxia-treated PASMCs were utilized for constructing an in-vitro pulmonary hypertension model. THP-1 cells were treated with PMA (320 nM) and LPS (10 μg/mL) + IFN-γ (20 ng/ml) for eliciting macrophage “M1” polarization. Exosomes derived from “M1” macrophages were isolated and added into PASMCs. The proliferation, inflammation, oxidative stress, and migration of PASMCs were evaluated. RT-PCR or Western blot examined the levels of miR-663b and the AMPK/Sirt1 pathway. Dual luciferase activity assay and RNA pull-down assay were carried out for confirming the targeted association between miR-663b and AMPK. An in-vivo PH model was built. Macrophage-derived exosomes with miR-663b inhibition were used for treating the rats, and alterations of pulmonary histopathology were monitored. Results: miR-663b was obviously up-regulated in hypoxia-elicited PASMCs and M1 macrophages. miR-663b overexpression boosted hypoxia-induced proliferation, inflammation, oxidative stress, and migration in PASMCs, whereas miR-663b low expression resulted in the opposite situation. AMPK was identified as a target of miR-663b, and miR-663b overexpression curbed the AMPK/Sirt1 pathway. AMPK activation ameliorated the damaging impact of miR-663b overexpression and “M1” macrophage exosomes on PASMCs. In vivo , “M1” macrophage exosomes with miR-663b low expression alleviated pulmonary vascular remodeling in pulmonary hypertension rats. Conclusion: Exosomal miR-663b from “M1” macrophage facilitates PASMC dysfunctions and PH development by dampening the AMPK/Sirt1 axis.

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MicroRNA in the Diagnosis and Treatment of Doxorubicin-Induced Cardiotoxicity

Cited by 8 publications

References 221 publications

Cucurbitacin IIa promotes the immunogenic cell death‑inducing effect of doxorubicin and modulates immune microenvironment in liver cancer

Cucurbitacin IIa promotes the immunogenic cell death‑inducing effect of doxorubicin and modulates immune microenvironment in liver cancer

Cardiac miRNA expression during the development of chronic anthracycline-induced cardiomyopathy using an experimental rabbit model

Exosomal miR-663b from “M1” macrophages promotes pulmonary artery vascular smooth muscle cell dysfunction through inhibiting the AMPK/Sirt1 axis

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