Identification of Cytochrome P450 2E1 as a Novel Target in Glioma and Development of Its Inhibitor as an Anti-Tumor Agent

Abstract

Glioblastoma (GBM) is a devastating inflammation-related cancer for which novel therapeutic targets are urgently required. Previous studies of the authors indicate Cytochrome P450 2E1 (CYP2E1) as a novel inflammatory target and develop a specific inhibitor Q11. Here it is demonstrated that CYP2E1 overexpression is closely related to higher malignancy in GBM patients. CYP2E1 activity is positively correlated with tumor weight in GBM rats. Significantly higher CYP2E1 expression accompanied by increased inflammation is detected in a mouse GBM model. Q11, 1-(4-methyl-5-thialzolyl) ethenone, a newly developed specific inhibitor of CYP2E1 here remarkably attenuates tumor growth and prolongs survival in vivo. Q11 does not directly affect tumor cells but blocks the tumor-promoting effect of microglia/macrophage (M/Mφ) in the tumor microenvironment through PPARγ-mediated activation of the STAT-1 and NF-κB pathways and inhibition of the STAT-3 and STAT-6 pathways. The effectiveness and safety of targeting CYP2E1 in GBM are further supported by studies with Cyp2e1 knockout rodents. In conclusion, a pro-GBM mechanism in which CYP2E1-PPARγ-STAT-1/NF-κB/STAT-3/STAT-6 axis fueled tumorigenesis by reprogramming M/Mφ and Q11 as a promising anti-inflammatory agent for GBM treatment is uncovered.

Keywords: CYP2E1; glioma; inflammation; microglia/macrophage; reprogramming; target; tumor microenvironment.