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ORIGINAL RESEARCH ARTICLE

In vitro suppression of glioblastoma cell functions by TG100-115, a transient receptor potential melastatin 7 kinase inhibitor

Yuanyuan Xu1,2 ,  Wenliang Chen1,2 ,  Rahmah Alanazi1,2 ,  Xinyang Zhang1,2 ,  Erin Cross2 ,  Barbara Gundi1,2 ,  James T. Rutka1 ,  F. David Horgen3 ,  Andrea Fleig4,5 ,  Zhong-Ping Feng2 ,  Hong-Shuo Sun1,2,6,7*
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1 Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
2 Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
3 Department of Natural Science, College of Natural Sciences and Computational Sciences, Hawaii Pacific University, Honolulu, Hawaii, United States of America
4 John A. Burns School of Medicine and University of Hawaii Cancer Center at the University of Hawaii at Manoa, Honolulu, Hawaii, United States of America
5 Center for Biomedical Research at The Queen’s Medical Center, Honolulu, Hawaii, United States of America
6 Department of Pharmacology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
7 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
Advanced Neurology, 025110023 https://doi.org/10.36922/AN025110023
Received: 14 March 2025 | Revised: 26 May 2025 | Accepted: 30 May 2025 | Published online: 11 July 2025
(This article belongs to the Special Issue Advanced Neurology 3rd Anniversary Special Issue)
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Glioblastomas (GBMs) are highly aggressive and lethal primary brain tumors, known for their rapid proliferation, diffuse infiltration, and resistance to conventional therapies. Recent studies have highlighted the involvement of transient receptor potential melastatin 7 (TRPM7) in regulating GBM progression through its dual function as an ion channel and a serine/threonine protein kinase. TG100-115, initially characterized as a phosphoinositide 3-kinase γ/δ inhibitor, has recently been identified as a novel inhibitor of TRPM7 kinase. However, its potential pharmacological effects in GBM cells have not been fully elucidated. In this study, we investigated the anti-GBM effects of TG100-115 in U251 glioma cells. Cell viability and proliferation were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, whereas cell motility and invasiveness were determined through wound healing and transwell assays, respectively. Western blotting was used to detect the expression of key proteins involved in the apoptotic and molecular signaling pathways. Our findings revealed that TG100-115 significantly diminished the viability of U251 cells by promoting apoptosis while concurrently inhibiting the migratory and invasive activities of GBM cells. Mechanistically, TG100-115 enhanced apoptotic signaling by modulating B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, and cleaved caspase-3 levels. It also altered the phosphorylation status of protein kinase B and cofilin – both critical for cell survival and cytoskeletal dynamics. In conclusion, these findings suggest that TG100-115, by targeting TRPM7 kinase, exhibits promising therapeutic potential for GBM treatment and provides novel insights into targeting TRPM7-associated pathways in aggressive brain tumors.

Graphical abstract
Keywords
Transient receptor potential melastatin 7 kinase
TG100-115
Glioblastoma
Proliferation
Migration
Invasion
Funding
This work was supported by the following grants: Canadian Institutes of Health Research (CIHR PJT-153155) to ZPF and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grants (RGPIN- 2016-04574 and RGPIN-2022-04589) to HSS.
Conflict of interest
Hong-Shuo Sun is an Editorial Board Member, and Zhong- Ping Feng serves as an Associate Editor for this journal, but they were not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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Advanced Neurology, Electronic ISSN: 2810-9619 Print ISSN: 3060-8589, Published by AccScience Publishing
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