Abstract C99: Wogonin enhanced reactive oxygen species-induced apoptosis and potentiated cytotoxic effects of chemotherapeutic agents by Nrf2 suppression in HepG2 cells.

Abstract

Abstract Abstract: Cancer cells, compared to normal cells, are under increased oxidative stress with higher level of ROS. When exposed to environmental or intracellular stresses like ROS, NFE-related factor 2 (Nrf2) is the key to antioxidant response by transcriptionally activate various detoxification and antioxidant enzymes. We have previously shown that wogonin (5,7-Dihydroxy-8-methoxy-2-phenyl-4H-1-benzopyran-4-one), a flavonoid isolated from the root of Scutellaria baicalensis Georgi, could reverse drug resistance in MCF-7/ DOX cells through blocking the translocation of Nrf2 into nucleus, however, the effects of wogonin on Nrf2 signaling pathway have not previously been reported. In our study, we observed that wogonin reduced Nrf2 nuclear translocation, and therefore elevated the level of intracellular ROS to accomplish the purpose of killing malignant cells. In order to confirm the roles of Nrf2, it was activated by tBHQ and knocked down by the Nrf2 siRNA, and the results demonstrated that the activation of Nrf2 was involved in the wogonin-induced accumulation of ROS and cell death. 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 through inducing phage II enzymes which sensitize cells to chemotherapeutic agents. On the other hand, inhibition of multidrug resistance-associated protein (MRPs) by wogonin to enhance the effective drug level in cancer cells is another way to potentiates chemotherapeutic effects. At last, we found that the down-regulation of Nrf2 is associated with over-expression of p53. Using p53 siRNA to knock down the endogenous p53 expression, the level of both c-Myc and Nrf2 in nucleus increased when exposed to wogonin. The present study indicated that wogonin can be used in chemotherapy not only because its own antitumor ability, but also due to the enhanced cytotoxic effects of chemotherapeutic agents. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C99. Citation Format: Chen Qian, Rong Hu. Wogonin enhanced reactive oxygen species-induced apoptosis and potentiated cytotoxic effects of chemotherapeutic agents by Nrf2 suppression in HepG2 cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C99.