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Omeprazole Inhibits Glioblastoma Cell Invasion and Tumor Growth
Background: The aryl hydrocarbon receptor (AhR) is expressed in gliomas and the highest staining is observed in glioblastomas. A recent study showed that the AhR exhibited tumor suppressor-like activity in established and patient-derived glioblastoma cells and genomic analysis showed that this was d...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465678/ https://www.ncbi.nlm.nih.gov/pubmed/32731514 http://dx.doi.org/10.3390/cancers12082097 |
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author | Jin, Un-Ho Michelhaugh, Sharon K. Polin, Lisa A. Shrestha, Rupesh Mittal, Sandeep Safe, Stephen |
author_facet | Jin, Un-Ho Michelhaugh, Sharon K. Polin, Lisa A. Shrestha, Rupesh Mittal, Sandeep Safe, Stephen |
author_sort | Jin, Un-Ho |
collection | PubMed |
description | Background: The aryl hydrocarbon receptor (AhR) is expressed in gliomas and the highest staining is observed in glioblastomas. A recent study showed that the AhR exhibited tumor suppressor-like activity in established and patient-derived glioblastoma cells and genomic analysis showed that this was due, in part, to suppression of CXCL12, CXCR4 and MMP9. Methods: Selective AhR modulators (SAhRMs) including AhR-active pharmaceuticals were screened for their inhibition of invasion using a spheroid invasion assay in patient-derived AhR-expressing 15-037 glioblastoma cells and in AhR-silenced 15-037 cells. Invasion, migration and cell proliferation were determined using spheroid invasion, Boyden chambers and scratch assay, and XTT metabolic assays for cell growth. Changes in gene and gene product expression were determined by real-time PCR and Western blot assays, respectively. In vivo antitumorigenic activity of omeprazole was determined in SCID mice bearing subcutaneous patient-derived 15-037 cells. Results: Results of a screening assay using patient-derived 15-037 cells (wild-type and AhR knockout) identified the AhR-active proton pump inhibitor omeprazole as an inhibitor of glioblastoma cell invasion and migration only AhR-expressing cells but not in cells where the AhR was downregulated. Omeprazole also enhanced AhR-dependent repression of the pro-invasion CXCL12, CXCR4 and MMP9 genes, and interactions and effectiveness of omeprazole plus temozolomide were response-dependent. Omeprazole (100 mg/kg/injection) inhibited and delayed tumors in SCID mice bearing patient-derived 15-037 cells injected subcutaneously. Conclusion: Our results demonstrate that omeprazole enhances AhR-dependent inhibition of glioblastoma invasion and highlights a potential new avenue for development of a novel therapeutic mechanism-based approach for treating glioblastoma. |
format | Online Article Text |
id | pubmed-7465678 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-74656782020-09-04 Omeprazole Inhibits Glioblastoma Cell Invasion and Tumor Growth Jin, Un-Ho Michelhaugh, Sharon K. Polin, Lisa A. Shrestha, Rupesh Mittal, Sandeep Safe, Stephen Cancers (Basel) Article Background: The aryl hydrocarbon receptor (AhR) is expressed in gliomas and the highest staining is observed in glioblastomas. A recent study showed that the AhR exhibited tumor suppressor-like activity in established and patient-derived glioblastoma cells and genomic analysis showed that this was due, in part, to suppression of CXCL12, CXCR4 and MMP9. Methods: Selective AhR modulators (SAhRMs) including AhR-active pharmaceuticals were screened for their inhibition of invasion using a spheroid invasion assay in patient-derived AhR-expressing 15-037 glioblastoma cells and in AhR-silenced 15-037 cells. Invasion, migration and cell proliferation were determined using spheroid invasion, Boyden chambers and scratch assay, and XTT metabolic assays for cell growth. Changes in gene and gene product expression were determined by real-time PCR and Western blot assays, respectively. In vivo antitumorigenic activity of omeprazole was determined in SCID mice bearing subcutaneous patient-derived 15-037 cells. Results: Results of a screening assay using patient-derived 15-037 cells (wild-type and AhR knockout) identified the AhR-active proton pump inhibitor omeprazole as an inhibitor of glioblastoma cell invasion and migration only AhR-expressing cells but not in cells where the AhR was downregulated. Omeprazole also enhanced AhR-dependent repression of the pro-invasion CXCL12, CXCR4 and MMP9 genes, and interactions and effectiveness of omeprazole plus temozolomide were response-dependent. Omeprazole (100 mg/kg/injection) inhibited and delayed tumors in SCID mice bearing patient-derived 15-037 cells injected subcutaneously. Conclusion: Our results demonstrate that omeprazole enhances AhR-dependent inhibition of glioblastoma invasion and highlights a potential new avenue for development of a novel therapeutic mechanism-based approach for treating glioblastoma. MDPI 2020-07-28 /pmc/articles/PMC7465678/ /pubmed/32731514 http://dx.doi.org/10.3390/cancers12082097 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Jin, Un-Ho Michelhaugh, Sharon K. Polin, Lisa A. Shrestha, Rupesh Mittal, Sandeep Safe, Stephen Omeprazole Inhibits Glioblastoma Cell Invasion and Tumor Growth |
title | Omeprazole Inhibits Glioblastoma Cell Invasion and Tumor Growth |
title_full | Omeprazole Inhibits Glioblastoma Cell Invasion and Tumor Growth |
title_fullStr | Omeprazole Inhibits Glioblastoma Cell Invasion and Tumor Growth |
title_full_unstemmed | Omeprazole Inhibits Glioblastoma Cell Invasion and Tumor Growth |
title_short | Omeprazole Inhibits Glioblastoma Cell Invasion and Tumor Growth |
title_sort | omeprazole inhibits glioblastoma cell invasion and tumor growth |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465678/ https://www.ncbi.nlm.nih.gov/pubmed/32731514 http://dx.doi.org/10.3390/cancers12082097 |
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