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PURPOSE: Doxorubicin (Dox) is clinically limited due to its dose-dependent cardiotoxicity. Andrographolide (Andro) has been confirmed to exert cardiovascular protective activities. This study aimed to investigate protective effects of Andro in Dox-induced cardiotoxicity (DIC). METHODS: The cardiotoxicity models were induced by Dox in vitro and in vivo. The viability and apoptosis of H9c2 cells and the myocardial function of c57BL/6 mice were accessed with and without Andro pretreatment. Network pharmacology and RNA-seq were employed to explore the mechanism of Andro in DIC. The protein levels of Bax, Bcl2, NLRP3, Caspase-1 p20, and IL-1ß were qualified as well. RESULTS: In vitro, Dox facilitated the downregulation of cell viability and upregulation of cell apoptosis, after Andro pretreatment, the above symptoms were remarkably reversed. In vivo, Andro could alleviate Dox-induced cardiac dysfunction and apoptosis, manifesting elevation of LVPWs, LVPWd, EF% and FS%, suppression of CK, CK-MB, c-Tnl and LDH, and inhibition of TUNEL-positive cells. Using network pharmacology, we collected and visualized 108 co-targets of Andro and DIC, which were associated with apoptosis, PI3K-AKT signaling pathway, and others. RNA-seq identified 276 differentially expressed genes, which were enriched in response to oxidative stress, protein phosphorylation, and others. Both network pharmacology and RNA-seq analysis identified Tap1 and Timp1 as key targets of Andro in DIC. RT-QPCR validation confirmed that the mRNA levels of Tap1 and Timp1 were consistent with the sequenced results. Moreover, the high expression of NLRP3, Caspase-1 p20, and IL-1ß in the Dox group was reduced by Andro. CONCLUSIONS: Andro could attenuate DIC through suppression of Tap1 and Timp1 and inhibition of NLRP3 inflammasome activation, serving as a promising cardioprotective drug.
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PURPOSE: Trastuzumab is a landmark agent in the treatment of human epidermal growth factor receptor-2(HER2)-positive breast cancer. Nevertheless, trastuzumab also comes with unexpected cardiac side effects. Hyperoside is a natural product that serves beneficial roles in cardiovascular disease. This study aimed to explore the effect and mechanism of hyperoside in trastuzumab-induced cardiotoxicity. METHODS: A female C57BL/6 mice cardiotoxicity model was established via intraperitoneally injecting with trastuzumab (10 mg/kg/day, once every other day, cumulative dosage to 40 mg/kg) with or without hyperoside (15 or 30 mg/kg/day) administration. In vitro, the H9c2 cells were exposed to 1 µM trastuzumab with or without hyperoside (100 or 200 µM) administration. Cardiac function was evaluated by echocardiographic, myocardial enzymes levels, and pathological section examinations. TUNEL staining and Annexin V-FITC/ propidium iodide flow cytometry were used to analyze the cardiomyocyte apoptosis. RESULTS: Compared to the control group, the LVEF, LVFS was decreased and the concentrations of cTnT, CK, CK-MB and LDH in mice were significantly increased after treatment with trastuzumab. Collagen deposition and cardiomyocyte hypertrophy were observed in the myocardium of the trastuzumab group. However, these changes were all reversed by different doses of hyperoside. In addition, hyperoside attenuated trastuzumab-induced myocardium apoptosis and H9c2 cells apoptosis through inhibiting the expressions of cleaved caspase-3 and Bax. Trastuzumab abolished the PI3K/Akt signaling pathway in mice and H9c2 cells, while co-treatment of hyperoside effectively increased the ratio of p-Akt/Akt. CONCLUSION: Hyperoside inhibited trastuzumab-induced cardiotoxicity through activating the PI3K/Akt signaling pathway. Hyperoside may be a promising therapeutic approach to trastuzumab-induced cardiotoxicity.
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Trastuzumab-induced cardiotoxicity (TIC) is a common and serious disease with abnormal cardiac function. Accumulating evidence has indicated certain non-coding RNAs (ncRNAs), functioning as competing endogenous RNAs (ceRNAs), impacting the progression of cardiovascular diseases. Nonetheless, the specific involvement of ncRNA-mediated ceRNA regulatory mechanisms in TIC remains elusive. The present research aims to comprehensively investigate changes in the expressions of all ncRNA using whole-transcriptome RNA sequencing. The sequencing analysis unveiled significant dysregulation, identifying a total of 43 circular RNAs (circRNAs), 270 long noncoding RNAs (lncRNAs), 12 microRNAs (miRNAs), and 4131 mRNAs in trastuzumab-treated mouse hearts. Subsequently, circRNA-based ceRNA networks consisting of 82 nodes and 91 edges, as well as lncRNA-based ceRNA networks comprising 111 nodes and 112 edges, were constructed. Using the CytoNCA plugin, pivotal genes-miR-31-5p and miR-644-5p-were identified within these networks, exhibiting potential relevance in TIC treatment. Additionally, KEGG and GO analyses were conducted to explore the functional pathways associated with the genes within the ceRNA networks. The outcomes of the predicted ceRNAs and bioinformatics analyses elucidated the plausible involvement of ncRNAs in TIC pathogenesis. This insight contributes to a better understanding of underlying mechanisms and aids in identifying promising targets for effective prevention and treatment strategies.
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Doxorubicin is a widely used anticancer drug in clinical practice for the treatment of various human tumors. However, its administration is associated with cardiotoxicity. Administration of doxorubicin with low side effects for cancer treatment and prevention are, accordingly, urgently required. The human body harbors various endogenous metal ions that exert substantial influences. Consequently, extensive research has been conducted over several decades to investigate the potential of targeting endogenous metal ions to mitigate doxorubicin's side effects and impede tumor progression. In recent years, there has been a growing body of research indicating the potential efficacy of metal ion-associated therapeutic strategies in inhibiting doxorubicin-induced cardiotoxicity (DIC). These strategies offer a combination of favorable safety profiles and potential clinical utility. Alterations in intracellular levels of metal ions have been found to either facilitate or mitigate the development of DIC. For instance, ferroptosis, a cellular death mechanism, and metal ions such as copper, zinc, and calcium have been identified as significant contributors to DIC. This understanding can contribute to advancements in cancer treatment and provide valuable insights for mitigating the cardiotoxic effects of other therapeutic drugs. Furthermore, potential therapeutic strategies have been investigated to alleviate DIC in clinical settings. The ultimate goal is to improve the efficacy and safety of Dox and offer valuable insights for future research in this field.
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Cardiotoxicity induced by anticancer drugs interferes with the continuation of optimal treatment, inducing life-threatening risks or leading to long-term morbidity. The heart is a complex pluricellular organ comprised of cardiomyocytes and non-cardiomyocytes. Although the study of these cell populations has been often focusing on cardiomyocytes, the contributions of non-cardiomyocytes to development and disease are increasingly being appreciated as both dynamic and essential. This review summarized the role of non-cardiomyocytes in anticancer drug-induced cardiotoxicity, including the mechanism of direct damage to resident non-cardiomyocytes, cardiomyocytes injury caused by paracrine modality, myocardial inflammation induced by transient cell populations and the protective agents that focused on non-cardiomyocytes.