Wogonin-enhanced reactive oxygen species-induced apoptosis and potentiated cytotoxic effects of chemotherapeutic agents by suppression Nrf2-mediated signaling in HepG2 cells

Cancer cells, compared with normal cells, are under increased oxidative stress with higher level of reactive oxygen species (ROS). When exposed to environmental stresses such as ROS, NFE-related factor 2 (Nrf2) is the key to antioxidant response by transcriptionally activating various detoxification and antioxidant enzymes. Previously, we have shown that wogonin, a flavonoid isolated from the root of Scutellaria baicalensis Georgi, could reverse drug resistance in MCF-7/DOX cells by blocking the translocation of Nrf2 into nucleus. However, the exact mechanism underlying the effect remains unclear. In this study, we observed that wogonin reduced the Nrf2 nuclear translocation, and therefore elevated the level of intracellular ROS to accomplish the purpose of killing malignant cells. Furthermore, the suppression of Nrf2 by wogonin can potentiate cytotoxic effects of chemotherapeutic agents in HepG2 cells. On one hand, down-regulation of Nrf2 lead to reduction of cytoprotective effect by inducing phage II enzymes which sensitize cells to chemotherapeutic agents. On the other hand, inhibition of multidrug resistance-associated proteins (MRPs) by wogonin enhances the effective drug level in cancer cells and potentiates their chemotherapeutic effects. Finally, we found that the decrease of Nrf2 may be related to overexpression of p53. Using p53 siRNA to knock down the endogenous p53 expression, the levels of both c-myc and Nrf2 in nucleus increased when exposed to wogonin. The present study indicates that wogonin can be used in chemotherapy not only because of its own antitumor ability, but also due to the enhanced cytotoxic effects of chemotherapeutic agents.