Breviscapine remodels myocardial glucose and lipid metabolism by regulating serotonin to alleviate doxorubicin-induced cardiotoxicity

Abstract

Aims: The broad-spectrum anticancer drug doxorubicin (Dox) is associated with a high incidence of cardiotoxicity, which severely affects the clinical application of the drug and patients’ quality of life. Here, we assess how Dox modulates myocardial energy and contractile function and this could aid the development of relevant protective drugs.Methods: Mice were subjected to doxorubicin and breviscapine treatment. Cardiac function was analyzed by echocardiography, and Dox-mediated signaling was assessed in isolated cardiomyocytes. The dual cardio-protective and anti-tumor actions of breviscapine were assessed in mouse breast tumor models.Results: We found that Dox disrupts myocardial energy metabolism by decreasing glucose uptake and increasing fatty acid oxidation, leading to a decrease in ATP production rate, an increase in oxygen consumption rate and oxidative stress, and further energy deficits to enhance myocardial fatty acid uptake and drive DIC development. Interestingly, breviscapine increases the efficiency of ATP production and restores myocardial energy homeostasis by modulating the serotonin-glucose-myocardial PI3K/AKT loop, increasing glucose utilization by the heart and reducing lipid oxidation. It enhances mitochondrial autophagy via the PINK1/Parkin pathway, eliminates damaged mitochondrial accumulation caused by Dox, reduces the degree of cardiac fibrosis and inflammation, and restores cardiac micro-environmental homeostasis. Importantly, its low inflammation levels reduce myeloid immunosuppressive cell infiltration, and this effect is synergistic with the anti-tumor effect of Dox.Conclusion: Our findings suggest that disruption of the cardiac metabolic network by Dox is an important driver of its cardiotoxicity and that serotonin is an important regulator of myocardial glucose and lipid metabolism. Myocardial energy homeostasis and timely clearance of damaged mitochondria synergistically contribute to the prevention of anthracycline-induced cardiotoxicity and improve the efficiency of tumor treatment.

Insights into Yeast Response to Chemotherapeutic Agent through Time Series Genome-Scale Metabolic Models

“…ATP production is also an important issue in cardio toxic side effect of doxorubicin. In human heart it is known that doxorubicin reduces ATP production efficiency [41]. Short term response of yeast cells might be simulating this phenomenon (Figure 2).…”

Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy

“…The clinical application of DOX is severely hampered by its dose-dependent cardiotoxicity and consequent heart failure ( Angsutararux et al, 2015 ), characterized by ROS overproduction, imbalance of mitochondrial dynamics ( Li et al, 2022 ), cardiac energy metabolism dysfunction and cardiomyocyte apoptosis ( Sterba et al, 2013 ). Dexrazoxane (DXZ) is currently the exclusive FDA approved drug for DOX induced cardiotoxicity treatment.…”

Breviscapine attenuates lead‑induced myocardial injury by activating the Nrf2 signaling pathway

“…It possesses a range of biological functions, including anti-inflammatory, antioxidant, anti-apoptotic and myocardial protection ( 7 ). Several studies have assessed its utility in the treatment of cardiovascular diseases, such as cardiac hypertrophy ( 8 ) and doxorubicin (DOX)-induced cardiotoxicity ( 9 ). Additionally, Bre has been shown to inhibit myocardial inflammation and apoptosis in rats with coronary embolisms ( 10 ) and exhibit protective effects against myocardial injuries induced by streptozotocin, thereby enhancing the antioxidant capacity of myocardial tissues ( 11 ).…”