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Repurposing T-type calcium channel blocker lomerizine as a therapeutic strategy for glioblastoma
Toshiya Ichinose1, Sho Tamai1, Nozomi Hirai2
1Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan.
Abstract:
Glioblastoma (GBM) is the most malignant primary brain tumor. The presence of glioma stem/initiating cells (GICs) is known to cause strong treatment resistance; therefore, GICs are a major target for GBM therapy, although there are no therapies targeting GICs clinically. To identify novel treatments for GBMs, we performed drug repurposing screening using GICs and identified the T-type calcium channel blocker lomerizine - a migraine prophylactic drug. Lomerizine inhibited proliferation, migration, invasion, and cell cycle progression and induced apoptosis in GICs and differentiated glioma cells. Lomerizine had antitumor effects by inactivating STAT3 in all cell lines. Furthermore, lomerizine also dephosphorylated AKT and ERK only in GICs and had strong tumor-suppressive ability. Lomerizine also reduced tumor volume and prolonged overall survival in vivo. Based on our data from in vitro and in vivo experiments, lomerizine has potential as a GBM therapeutic agent targeting both GICs and differentiated glioma cells and could benefit GBM patients.
Insights
Lomerizine, a migraine drug, shows promise in treating glioblastoma (GBM). It targets both glioma stem cells and differentiated cells, inhibiting tumor growth and improving survival in preclinical models.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Pharmacology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor known for treatment resistance.
- Glioma stem/initiating cells (GICs) drive GBM's resistance, posing a significant therapeutic challenge.
- Current therapies lack specific GIC-targeting agents.
Purpose of the Study:
- To identify novel glioblastoma (GBM) therapies through drug repositioning.
- To investigate the efficacy of T-type calcium channel blocker lomerizine against GBM, particularly GICs.
Main Methods:
- Drug repositioning screening utilizing GICs.
- In vitro assays assessing proliferation, migration, invasion, cell cycle, and apoptosis.
- In vivo studies evaluating tumor volume and overall survival.
- Analysis of signaling pathways including STAT3, AKT, and ERK.
Main Results:
- Lomerizine demonstrated significant inhibition of GBM cell proliferation, migration, invasion, and cell cycle progression.
- Lomerizine induced apoptosis in both GICs and differentiated glioma cells.
- Antitumor effects were mediated by STAT3 inactivation, with additional dephosphorylation of AKT and ERK observed specifically in GICs.
- In vivo experiments showed reduced tumor volume and prolonged survival in GBM models.
Conclusions:
- Lomerizine exhibits potent anti-GBM activity by targeting both GICs and differentiated glioma cells.
- The drug's mechanism involves inactivation of STAT3 and modulation of AKT/ERK signaling in GICs.
- Lomerizine presents a promising therapeutic candidate for glioblastoma treatment, potentially benefiting patients.
