Berberine Enhances Chemosensitivity and Induces Apoptosis Through Dose-orchestrated AMPK Signaling in Breast Cancer

Breast cancer is the most common malignancy in women. Although personalized or targeting molecular cancer therapy is more popular up to now, the cytotoxicity chemotherapy for patients with advanced breast cancer is considered as the alternative option. However, chemoresistance is still the common and critical limitation for breast cancer treatment. Berberine, known as AMPK activator, has shown multiple activities including antitumor effect. In this study, we investigate the chemosensitive effect of different dosages berberine on drug-resistant human breast cancer MCF-7/MDR cell in vitro and in vivo, and the mechanisms underlying AMPK activation on Doxorubicin (DOX) chemosensitivity. Our results showed that berberine could overcome DOX resistance in dose-orchestrated manner: On one hand, low-dose berberine can enhance DOX sensitivity in drug-resistance breast cancer cells through AMPK-HIF-1 alpha-P-gp pathway. On the other hand, high-dose berberine alone directly induces apoptosis through the AMPK-p53 pathway with the independence of HIF-1 alpha expression. Taken together, our findings demonstrate that berberine sensitizes drug-resistant breast cancer to DOX chemotherapy and directly induces apoptosis through the dose-orchestrated AMPK signaling pathway in vitro and in vivo. Berberine appears to be a promising chemosensitizer and chemotherapeutic drug for breast cancer treatment.