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Astragaloside IV Reduces Sorafenib-Induced Cardiotoxicity by Inhibiting Apoptosis Through the STAT3/HIF-1α/Bcl-2
Lei Wang1, Baonian Liu1, Qianhui You1
1Department of Anatomy, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Abstract:
Sorafenib is a first-line tyrosine kinase inhibitor for malignant tumor treatment, yet its clinical application is greatly restricted by unavoidable cardiotoxicity. Astragaloside IV is a natural compound with prominent cardiovascular protective effects. We first carried out modeling studies including network pharmacology, human proteome microarray screening, molecular docking, and molecular dynamics simulation. Network pharmacology highlighted the hypoxia-inducible factor-1 signaling pathway as a key route; the integrated approach further identified signal transducer and activator of transcription 3 as a novel direct binding target of astragaloside IV with high binding stability. In a mouse model of chronic sorafenib-induced cardiotoxicity, astragaloside IV significantly improved cardiac function, and attenuated myocardial fibrosis, oxidative damage, and cardiomyocyte apoptosis. Mechanistically, astragaloside IV reduced the expression of signal transducer and activator of transcription 3 and hypoxia-inducible transcription factor-1α, and elevated the expression of B-cell lymphoma 2. In cellular experiments, astragaloside IV protected HL-1 cardiomyocytes against sorafenib-induced cytotoxicity and apoptosis through the same signaling pathway. This study confirms that astragaloside IV alleviates sorafenib-induced cardiotoxicity by inhibiting cardiomyocyte apoptosis via targeting the signal transducer and activator of transcription 3/hypoxia-inducible transcription factor-1α/B-cell lymphoma 2 pathway, providing a promising strategy for clinical prevention of chemotherapy-related cardiac injury.
Insights
Astragaloside IV protects the heart from sorafenib damage by reducing cardiomyocyte apoptosis. This natural compound targets the signal transducer and activator of transcription 3/hypoxia-inducible transcription factor-1α/B-cell lymphoma 2 pathway, offering a strategy against chemotherapy-related cardiac injury.
Area of Science:
- Cardiovascular Pharmacology
- Natural Product Chemistry
- Oncology Drug Safety
Background:
- Sorafenib, a tyrosine kinase inhibitor, is vital for cancer treatment but causes significant cardiotoxicity.
- Astragaloside IV, a natural compound, exhibits known cardiovascular protective properties.
- Developing strategies to mitigate chemotherapy-induced cardiotoxicity is crucial for patient outcomes.
Purpose of the Study:
- To investigate the protective effects of Astragaloside IV against sorafenib-induced cardiotoxicity.
- To elucidate the underlying molecular mechanisms of Astragaloside IV's cardioprotective action.
- To identify novel therapeutic targets for preventing chemotherapy-related cardiac injury.
Main Methods:
- Network pharmacology and human proteome microarray screening identified key pathways and targets.
- Molecular docking and dynamics simulations assessed binding stability of Astragaloside IV.
- In vivo mouse models and in vitro cellular experiments evaluated Astragaloside IV's efficacy and mechanism.
Main Results:
- Astragaloside IV significantly improved cardiac function and reduced myocardial fibrosis, oxidative damage, and apoptosis in a mouse model.
- Mechanistically, Astragaloside IV inhibited signal transducer and activator of transcription 3 (STAT3) and hypoxia-inducible transcription factor-1α (HIF-1α) expression, while increasing B-cell lymphoma 2 (Bcl-2) expression.
- Astragaloside IV protected HL-1 cardiomyocytes from sorafenib-induced cytotoxicity and apoptosis via the STAT3/HIF-1α/Bcl-2 pathway.
Conclusions:
- Astragaloside IV effectively alleviates sorafenib-induced cardiotoxicity by inhibiting cardiomyocyte apoptosis.
- The cardioprotective mechanism involves targeting the STAT3/HIF-1α/Bcl-2 signaling pathway.
- Astragaloside IV presents a promising therapeutic strategy for preventing chemotherapy-related cardiac injury.
