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Published on: March 28, 2021
Identification of Cytochrome P450 2E1 as a Novel Target in Glioma and Development of Its Inhibitor as an Anti-Tumor
Guiming Hu1,2, Yan Fang1,2, Haiwei Xu3
1Institute of Clinical Pharmacology, Zhengzhou University, Kexue Road, Zhengzhou, 450001, China.
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.
Insights
Targeting Cytochrome P450 2E1 (CYP2E1) with inhibitor Q11 shows promise for glioblastoma (GBM). Q11 reduces GBM growth by modulating microglia/macrophage inflammation pathways, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Glioblastoma (GBM) is an aggressive brain cancer linked to inflammation.
- Novel therapeutic targets are needed for GBM treatment.
- Cytochrome P450 2E1 (CYP2E1) is implicated in GBM's inflammatory nature.
Purpose of the Study:
- To investigate the role of CYP2E1 in GBM.
- To evaluate the efficacy of a novel CYP2E1 inhibitor, Q11, in GBM treatment.
- To elucidate the molecular mechanisms underlying Q11's anti-GBM effects.
Main Methods:
- Assessed CYP2E1 expression and activity in GBM patient data and animal models.
- Administered Q11 to GBM-bearing rodents to evaluate tumor growth and survival.
- Investigated Q11's effects on microglia/macrophage (M/Mφ) function and signaling pathways (PPARγ, STATs, NF-κB).
- Utilized Cyp2e1 knockout rodents to confirm target specificity.
Main Results:
- CYP2E1 overexpression correlates with higher GBM malignancy and tumor weight.
- Q11 significantly inhibited GBM tumor growth and improved survival in vivo.
- Q11 acts by reprogramming M/Mφ via the CYP2E1-PPARγ-STAT-1/NF-κB/STAT-3/STAT-6 axis.
- Studies in knockout rodents validated the safety and effectiveness of targeting CYP2E1.
Conclusions:
- CYP2E1 plays a crucial role in GBM tumorigenesis by promoting inflammation through M/Mφ reprogramming.
- The identified CYP2E1-PPARγ-STAT axis offers a novel therapeutic target for GBM.
- Q11 demonstrates potential as an anti-inflammatory therapeutic agent for GBM treatment.
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