UPLC-Q-TOF-MS based investigation into the bioactive compounds and molecular mechanisms of Qishen Huanwu capsule attenuates anthracycline-induced cardiotoxicity

Background

Cardiotoxicity is a prevalent side effect linked to anthracyclines, a class of chemotherapy drugs, that frequently leads to the discontinuation of anthracycline-based treatments among cancer patients. Thus, there is a pressing need to mitigate and prevent these cardiotoxic effects. Mounting evidence suggests that Traditional Chinese Medicine may alleviate the toxic side effects of chemotherapy agents. For this reason, this study seeked to comprehensively assess the cardioprotective properties of the Qishen Huanwu capsule (QSHWC) against pirarubicin (THP)-induced cardiotoxicity in rat models and explore the underlying mechanisms.

Methods

The effects of QSHWC on anthracycline-induced myocyte damage was evaluated via CCK8 assay. Investigations conducted subsequently principally comprised network pharmacology methodology, Ultra-performance liquid chromatograph-hybrid quadrupole orbitrap high resolution mass spectrometer (UHPLC-Q-Orbitrap HRMS) and an anthracycline-induced cardiotoxicity (AIC) rat model to dig into the chemical constituents and potential therapeutic mechanisms of the QSHWC.

Results

As evidently demonstrated by in-vitro studies, QSHWC not only effectively elevated the cell viability of H9c2 after anthracycline injury, but also downregulates NLRP3 expression and LDH release. As illustrated by in-vivo studies, medium and high doses of QSHWC improved the cardiac injury caused by pirarubicin, decreased myocardial injury scores, cTnT and NT-proBNP levels, and elevated the left ventricular ejection fraction (LVEF %). By conducting HPLC-Q-Exactive-MS analysis, we identified the major parts of the QSHWC. As suggested by network pharmacology and molecular docking analyses, QSHWC may exert cardioprotective protective effects by regulating multiple signaling pathways such as PI3K/AKT and NOD-like receptors. Last but not least, animal experiments confirmed that QSHWC can up-regulate phosphorylated PI3K and phosphorylated AKT in rat myocardial tissue, while down-regulating NLRP3 levels.

Conclusion

QSHWC alleviates anthracycline-induced cardiotoxicity by targeting cardiac pyroptosis through the PI3K/AKT pathway, while providing a multi-target therapeutic strategy.