The Role of Nrf2 in Glioma: Therapeutic Targeting Strategies.

Abstract

Cancer is one of the most challenging diseases to cure due to its complexity. Gli-oma, as a neuroepithelial cancer of the glial cells, is one of the rarest malignancies which has a low survival rate. The exact risk factors of glioma are still not clear, but allergy, ionizing radiation, and hereditary factors are reported to be associated with glioma. Nrf2 as an antiox-idant regulator has been reported to be highly expressed in malignances tissues like glioma. Nrf2 regulates the expression of various antioxidant and cytoprotective genes. In gliomas, Nrf2 activation helps tumor cells combat oxidative stress by enhancing the production of de-toxifying enzymes (e.g., glutathione peroxidase, NADPH quinone oxidoreductase). This al-lows glioma cells to survive and proliferate in toxic tumor microenvironments rich in reactive oxygen species (ROS). Although the role of Nrf2 in the apoptosis of cancerous glial cells is not clear yet, it has been shown that Nrf2 inhibition via different methods can increase the efficiency of the chemo-therapy agents to treat glioma. Elevated Nrf2 activity has been linked to drug resistance in gliomas. The activation of Nrf2 increases the expression of multidrug resistance-associated proteins (MRPs) and other detoxifying enzymes, which limit the effectiveness of chemother-apeutic agents like temozolomide (TMZ). Nrf2 inhibitors can suppress the signaling pathway of Nrf2 and decrease the expression of detoxifying enzymes like SOD, CAT, GPX, and GCL, which can increase the efficiency of chemotherapy agents. Using drugs that inhibit the Nrf2 expression in combination with classical chemotherapy agents can be a promising procedure to decrease chemoresistance and be effective in increasing the survival rate of patients with glioma. In this study, we focused on the association of glioma and Nrf2 expression and its targeting as a new therapeutic approach in glioma treatment.