Identification of repaglinide as a therapeutic drug for glioblastoma multiforme.

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients.

• Authors: Zui Xuan Xiao, Ruo Qiao Chen, Dian Xing Hu, Xiao Qiang Xie, Shang Bin Yu, Xiao Qian Chen
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 488 Issue 1 Pg. 33-39 (06 17 2017) ISSN: 1090-2104 [Electronic] United States
• PMID: 28476618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017. Published by Elsevier Inc.

Chemical References

• Carbamates
• Piperidines
• repaglinide

Topics

• Animals
• Carbamates (administration & dosage, pharmacology, therapeutic use)
• Cell Survival (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Glioblastoma (drug therapy, metabolism, pathology)
• Humans
• Mice
• Mice, Inbred C57BL
• Piperidines (administration & dosage, pharmacology, therapeutic use)
• Structure-Activity Relationship
• Tumor Cells, Cultured