The NF-E2 family transcription factor Nrf2 plays a critical role in the up-regulation of a battery of genes encoding detoxifying enzymes, antioxidant-modulating enzymes and the 26S proteasome. Now, it is widely accepted that Nrf2 is an essential element for the mammalian defense system against oxidative damage. However, there have been several lines of evidence supporting that Nrf2 may participate in the resistance of cancer cells by facilitating detoxication of anticancer agents. In our current study, it has been found that human ovarian cancer cell A2780, which is highly sensitive to doxorubicin and cisplatin, shows low levels of the ARE binding activity and the ARE-derived luciferase activity, as well as the repressed expression of Nrf2-target genes compared with resistant ovarian cancer cells. Acquisition of the resistance following a prolonged exposure of A2780 cells to doxorubicin was accompanied with the elevation of the ARE-Nrf2 pathway and resulted increase in total GSH contents. While, the chemoresistance of SK-OV3 ovarian cancer cells was in part, associated with high level of the Nrf2 pathway and functional inhibition of Nrf2 by using siRNA could sensitize SK-OV3 to anticancer agents. These results indicate that effective modulation of Nrf2, which plays a protective role in normal cells, might be a promising strategy to control the chemoresistance of ovarian cancer cells.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5525.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO