Background Glioblastoma (GBM) is a universally lethal tumor with frequently overexpressed or mutated epidermal growth factor receptor (EGFR). NADPH quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and promotes GBM cell proliferation. Methods High-throughput screen was used for agents selectively active against GBM cells with EGFRvIII mutations. Co-crystal structures were revealed molecular details of target recognition. Pharmacological and gene knockdown/overexpression approaches were used to investigate the oxidative stress in vitro and in vivo. Results We identified a small molecular inhibitor, “MNPC,” that binds to both NQO1 and GSTP1 with high affinity and selectivity. MNPC inhibits NQO1 and GSTP1 enzymes and induces apoptosis in GBM, specifically inhibiting the growth of cell lines and primary GBM bearing the EGFRvIII mutation. Co-crystal structures between MNPC and NQO1, and molecular docking of MNPC with GSTP1 reveal that it binds the active sites and acts as a potent dual inhibitor. Inactivation of both NQO1 and GSTP1 with siRNA or MNPC results in imbalanced redox homeostasis, leading to apoptosis and mitigated cancer proliferation in vitro and in vivo. Conclusions Thus, MNPC, a dual inhibitor for both NQO1 and GSTP1, provides a novel lead compound for treating GBM via the exploitation of specific vulnerabilities created by mutant EGFR.
Renal cancer is one of the most common malignant tumors with high mortality, and kidney renal clear cell carcinoma (KIRC) is the most common type of renal cancer. We attempted to evaluate the clinical and prognostic significance of Apolipoprotein A1 (APOA1) mRNA and protein in KIRC patients. Clinical data along with RNA-sequencing data were downloaded from UCSC Xena. The Human Protein Atlas database was searched to reveal APOA1 protein expression profiles in KIRC and normal renal tissues. The TIMER database was applied to determine the correlations of APOA1 with immune cells and PD-1 and PD-L1 in KIRC. Ninety-one cases of KIRC patients and 93 healthy controls from our hospital were enrolled for clinical validation. Levels of APOA1 mRNA in KIRC tissues (N = 535) are not only lower than the levels in normal renal tissues (N = 117), but also in paired normal renal tissues (N = 72). High expression of APOA1 mRNA at the time of surgery was correlated with worse overall survival (OS) (HR 1.66; p = 0.037) and disease-free survival (DFS) (HR 1.65; p = 0.047), and APOA1 DNA methylation was linked to worse OS (HR 2.1; p = 0.001) rather than DFS (HR 1.12; p = 0.624) in KIRC patients. Concentrations of preoperative serum APOA1 protein were markedly decreased in KIRC patients compared to healthy controls (p < 0.01), and low levels of APOA1 protein predicted less favorable OS than those with high levels (HR = 2.84, p = 0.0407). APOA1 negatively correlated with various immune cell infiltrates and PD-L1 expression (r = − 0.283, p = 2.74e−11) according to the TIMER database. Low levels of APOA1 mRNA at the time of surgery predict favorable survival in KIRC patients. Our results provide insights to identify a novel prognostic index with great clinical utility.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.