Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox- sensitive transcription factor regulating expression of a number of cytoprotective genes. Recently, Nrf2 has emerged as an important contributor to chemoresistance in cancer therapy. In the present study, we found that non-toxic dose of apigenin (APG) significantly sensitizes doxorubicin-resistant BEL-7402 (BEL-7402/ADM) cells to doxorubicin (ADM) and increases intracellular concentration of ADM. Mechanistically, APG dramatically reduced Nrf2 expression at both the messenger RNA and protein levels through downregulation of PI3K/Akt pathway, leading to a reduction of Nrf2-downstream genes. In BEL-7402 xenografts, APG and ADM cotreatment inhibited tumor growth, reduced cell proliferation and induced apoptosis more substantially when compared with ADM treatment alone. These results clearly demonstrate that APG can be used as an effective adjuvant sensitizer to prevent chemoresistance by downregulating Nrf2 signaling pathway.