Omeprazole Inhibits Glioblastoma Cell Invasion and Tumor Growth.

Un-Ho Jin,Rupesh Shrestha,Sandeep Mittal,Lisa A Polin,Sharon K Michelhaugh,Stephen Safe

doi:10.3390/cancers12082097

Abstract

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.

Highlights

An estimated 23,880 new cases of cancer of the brain and nervous system are diagnosed each year and 16,380 deaths will occur from these diseases annually [1,2]
The aryl hydrocarbon receptor (AhR) is expressed in both established GBM cell lines and PDG cells and results of knockdown studies show that the AhR inhibits migration/invasion in GBM cells and we observed that neither kynurenine or TCDD affected GBM cell invasion [29]
AhR-active compounds including pharmaceuticals to determine their effects on a spheroid invasion in patient-derived 15-037 cells and cells in which the AhR has been knocked down by RNA interference (RNAi) (15-037 siAhR) or by CRISPR/Cas9 (15-037 AKO-19)

Summary

Introduction

An estimated 23,880 new cases of cancer of the brain and nervous system are diagnosed each year and 16,380 deaths will occur from these diseases annually [1,2]. Glioblastoma (GBM) is the most frequently diagnosed malignant primary brain tumor and global incidence of this disease varies from 0.59–3.69 per 100,000 [3]. 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. Results: Results of a screening assay using patient-derived 15-037 cells (wild-type and AhR knockout) identified the

Methods

Results

Discussion

Conclusion