Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

J Hematol Oncol, 2020 · DOI: https://doi.org/10.1186/s13045-020-00979-y · Published: October 13, 2020

Simple Explanation

Glioblastoma (GBM) is a deadly brain tumor where EGFR is often mutated or overexpressed. NQO1 and GSTP1 are also upregulated in GBM. These enzymes lower reactive oxygen species (ROS), mediating oxidative stress and promoting GBM cell proliferation. Researchers identified MNPC, a molecule that inhibits both NQO1 and GSTP1, binding with high affinity and selectivity. MNPC induces apoptosis in GBM, especially in cells with the EGFRvIII mutation. MNPC blocks the active sites of NQO1 and GSTP1, disrupting redox balance, causing apoptosis, and reducing cancer proliferation in lab and animal models. This suggests MNPC is a potential GBM treatment by targeting vulnerabilities from mutant EGFR.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Not specified

Key Findings

1
MNPC is a small molecule inhibitor that binds to both NQO1 and GSTP1 with high affinity and selectivity, inhibiting their enzymatic activities.
2
Inactivation of NQO1 and GSTP1 with siRNA or MNPC results in imbalanced redox homeostasis, leading to apoptosis and mitigated cancer proliferation in vitro and in vivo.
3
MNPC blocks GBM propagation and prolonged the survival rate in mice-bearing orthotopic tumors derived from EGFRvIII-positive cells.

Research Summary

This study identifies MNPC, a dual inhibitor of NQO1 and GSTP1, as a potential therapeutic agent for glioblastoma (GBM). MNPC selectively inhibits the proliferation of GBM cells bearing the EGFRvIII mutation by disrupting redox homeostasis. Structural analysis reveals that MNPC binds to the active sites of both NQO1 and GSTP1, inhibiting their enzymatic activities and leading to increased oxidative stress and apoptosis in GBM cells. In vivo experiments demonstrate that MNPC inhibits intracranial growth of U87MG/EGFRvIII cells and prolongs mouse survival, suggesting its potential as a novel therapeutic strategy for GBM.

Practical Implications

Drug development

MNPC provides a novel lead compound for treating GBM via exploitation of specific vulnerabilities created by mutant EGFR.

Therapeutic strategy

Targeting NQO1 and GSTP1 represents a promising therapeutic strategy for EGFRvIII-expressing GBM.

Repurposing potential

Nitazoxanide (NTZ) and Tizoxanide (TIZ) may be repurposed for treating GBM due to their similar structure–activity relationship with MNPC.

Study Limitations

1
The precise mechanism of oncogenesis of EGFRvIII is not entirely clear.
2
The relative efficacy of MNPC as compared to NTZ and TIZ in vivo remains to be determined.
3
The datasets generated and analyzed during the current study are not publicly available due to the ongoing study.

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