Chalcone-enriched fraction protects against chemotherapy-induced cardiotoxicity by restoring mitochondrial function and reducing oxidative stress

Background Natural compounds have demonstrated significant potential in mitigating chemotherapy-induced cardiotoxicity (CICT), primarily through their ability to alleviate oxidative stress and restore mitochondrial function. Purpose This study explored the cardioprotective and anticancer potential of a chalcone-enriched fraction (CEF) using an in vitro model of doxorubicin (Dox)-induced cytotoxicity in cardiomyocytes and breast cancer cells. Methods Cardiomyocytes were exposed to a 6-day Dox treatment with and without CEF co-treatment. Mitochondrial bioenergetics, oxidative stress, and inflammatory markers were evaluated using flow cytometry and ELISAs. Western blotting was conducted to assess the expression of mitochondrial signaling and autophagic markers. The anticancer activity of CEF was also assessed in breast cancer cells treated with Dox for the same duration. Results As a co-treatment with Dox, CEF significantly reduced Dox-induced inflammation and oxidative stress, evidenced by a reduction in IL-6 (p<0.001), IL-1β (p<0.05), malondialdehyde(p<0.001), and H₂O₂ (p<0.001) activity, while enhancing glutathione (p<0.001) and superoxide dismutase activities (p<0.001). CEF also improved mitochondrial respiration, including basal (p<0.05) and maximal respiration (p<0.01), state apparent (2.0±0.1 vs 3.1±0.1), respiratory control ratio (35.9±5.3 vs 12.7±2.7), and mitochondrial membrane potential (p<0.001). Autophagy markers, such as p-mTOR and Beclin-1, were significantly upregulated (p<0.05) in CEF-co-treated cardiomyocytes, suggesting an enhanced autophagic response. Additionally, proteins involved in cellular energy metabolism, including PGC1-α (p<0.05), pAMPK (p<0.001), PI3K(p<0.01), and Akt (p<0.01), were upregulated, further indicating CEF’s ability to enhance mitochondrial bioenergetics. In contrast, while CEF showed limited anticancer activity, no significant differences were observed in mitochondrial function or apoptosis in Dox-treated breast cancer cells co-treated with CEF compared to Dox alone. Conclusion These preliminary findings suggest that CEF offers significant cardioprotective benefits against CICT by mitigating Dox-induced oxidative stress and mitochondrial dysfunction, without compromising the efficacy of Dox. Further investigations are needed to validate these effects and explore the underlying mechanisms of CEF’s therapeutic properties.