Cargando…

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

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 re...

Descripción completa

Detalles Bibliográficos
Autores principales: Lei, Kecheng, Gu, Xiaoxia, Alvarado, Alvaro G., Du, Yuhong, Luo, Shilin, Ahn, Eun Hee, Kang, Seong Su, Ji, Bing, Liu, Xia, Mao, Hui, Fu, Haian, Kornblum, Harley I., Jin, Lingjing, Li, Hua, Ye, Keqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579906/
https://www.ncbi.nlm.nih.gov/pubmed/33087132
http://dx.doi.org/10.1186/s13045-020-00979-y
_version_ 1783598688712523776
author Lei, Kecheng
Gu, Xiaoxia
Alvarado, Alvaro G.
Du, Yuhong
Luo, Shilin
Ahn, Eun Hee
Kang, Seong Su
Ji, Bing
Liu, Xia
Mao, Hui
Fu, Haian
Kornblum, Harley I.
Jin, Lingjing
Li, Hua
Ye, Keqiang
author_facet Lei, Kecheng
Gu, Xiaoxia
Alvarado, Alvaro G.
Du, Yuhong
Luo, Shilin
Ahn, Eun Hee
Kang, Seong Su
Ji, Bing
Liu, Xia
Mao, Hui
Fu, Haian
Kornblum, Harley I.
Jin, Lingjing
Li, Hua
Ye, Keqiang
author_sort Lei, Kecheng
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7579906
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-75799062020-10-22 Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma Lei, Kecheng Gu, Xiaoxia Alvarado, Alvaro G. Du, Yuhong Luo, Shilin Ahn, Eun Hee Kang, Seong Su Ji, Bing Liu, Xia Mao, Hui Fu, Haian Kornblum, Harley I. Jin, Lingjing Li, Hua Ye, Keqiang J Hematol Oncol Research 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. BioMed Central 2020-10-21 /pmc/articles/PMC7579906/ /pubmed/33087132 http://dx.doi.org/10.1186/s13045-020-00979-y Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Lei, Kecheng
Gu, Xiaoxia
Alvarado, Alvaro G.
Du, Yuhong
Luo, Shilin
Ahn, Eun Hee
Kang, Seong Su
Ji, Bing
Liu, Xia
Mao, Hui
Fu, Haian
Kornblum, Harley I.
Jin, Lingjing
Li, Hua
Ye, Keqiang
Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma
title Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma
title_full Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma
title_fullStr Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma
title_full_unstemmed Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma
title_short Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma
title_sort discovery of a dual inhibitor of nqo1 and gstp1 for treating glioblastoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579906/
https://www.ncbi.nlm.nih.gov/pubmed/33087132
http://dx.doi.org/10.1186/s13045-020-00979-y
work_keys_str_mv AT leikecheng discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT guxiaoxia discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT alvaradoalvarog discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT duyuhong discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT luoshilin discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT ahneunhee discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT kangseongsu discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT jibing discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT liuxia discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT maohui discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT fuhaian discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT kornblumharleyi discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT jinlingjing discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT lihua discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma
AT yekeqiang discoveryofadualinhibitorofnqo1andgstp1fortreatingglioblastoma