Enhanced antitumor activity and attenuated cardiotoxicity of Epirubicin combined with Paeonol against breast cancer

Epirubicin is widely used for the therapy of various breast cancers. However, it has serious adverse side effects, particularly cardiotoxicity, which can cause irreversible damage in patients. Paeonol, an active component from Moutan Cortex, enhances antitumor activity of antineoplastics and reduces toxicities induced by chemotherapeutics. In this study, we investigated the anticancer activity of Paeonol in combination with Epirubicin against breast cancer and the alleviated effect of Paeonol on cardiotoxicity induced by Epirubicin. The apoptosis results and the coefficient of drug interaction values suggested significantly synergistic in combination of Paeonol and Epirubicin to 4T1 and MCF-7 cells. We further examined antitumor activities of Paeonol or/and Epirubicin in vivo in BALB/c mice and found that co-treatment of Paeonol and Epirubicin had a synergistic inhibitory effect on tumor growth and enhanced apoptosis in tumors in vivo compared with Epirubicin alone. Increased apoptosis was associated with the activation of apoptosis-related proteins including PARP, Bax, caspase 3, and inhibition of p38/JNK/ERK MAPKs. Moreover, Paeonol exhibited a mitigative effect on Epirubicin-induced cardiotoxicity through suppressing NF-kB pathway. In conclusion, Paeonol (a) enhanced the antitumor activity of Epirubicin in a synergistic manner against breast cancer cells via inhibiting p38/JNK/ERK MAPKs and (b) alleviated Epirubicin-induced cardiotoxicity by suppressing NF-kB pathway. These findings suggest that combination of Paeonol and Epirubicin is potentially applicable for breast cancer treatment.