Repurposing T-type calcium channel blocker lomerizine as a therapeutic strategy for glioblastoma
Toshiya Ichinose, Sho Tamai, Nozomi Hirai, Takashi Maejima, Kosuke Nambu, Hemragul Sabit, Shingo Tanaka, Masashi Kinoshita, Masahiko Kobayashi, Michihiro Mieda, Atsushi Hirao, Mitsutoshi Nakada
Toshiya Ichinose, Sho Tamai, Nozomi Hirai, Takashi Maejima, Kosuke Nambu, Hemragul Sabit, Shingo Tanaka, Masashi Kinoshita, Masahiko Kobayashi, Michihiro Mieda, Atsushi Hirao, Mitsutoshi Nakada
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Research Article Cell biology Oncology

Repurposing T-type calcium channel blocker lomerizine as a therapeutic strategy for glioblastoma

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.

Authors

Toshiya Ichinose, Sho Tamai, Nozomi Hirai, Takashi Maejima, Kosuke Nambu, Hemragul Sabit, Shingo Tanaka, Masashi Kinoshita, Masahiko Kobayashi, Michihiro Mieda, Atsushi Hirao, Mitsutoshi Nakada

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Figure 7

Effects of lomerizine on the AKT and ERK signaling pathway of glioblastoma cells.

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Effects of lomerizine on the AKT and ERK signaling pathway of glioblasto...
Western blotting of 3 GICs (KGS01, KGS10, and KGS15) and their differentiated cells (DKGS01, DKGS10, and DKGS15) (A and B) and 4 human glioma cell lines (U87, T98, A172, and SNB19) (C and D) treated with lomerizine. All glioma cells were treated with lomerizine at 0 (DMSO), 1, and 5 μM. Western blotting was performed on each cell line after 12 hours of exposure. The analyzed proteins included AKT, ERK, phospho-AKT (p-AKT), and phospho-ERK (p-ERK). The relative levels of protein expression were normalized to β-actin, serving as an internal control. The band intensity was analyzed via Western blotting using a CS analyzer. (A) Western blotting results for expression of AKT, p-AKT, ERK, and p-ERK in the 3 GICs and their differentiated cells. Expression of p-AKT and p-ERK was suppressed in all GICs and in partially differentiated GICs. (B) The average phosphorylation ratio of AKT and ERK expression in the 3 GIC cell lines and their differentiated cells was quantified using Western blotting. (C) Western blotting results for expression of AKT, p-AKT, ERK, and p-ERK in the 4 human glioma cell lines. Expression of p-AKT and p-ERK was partially suppressed in glioma cell lines. (D) The average phosphorylation ratios of AKT and ERK in the 4 glioma cell lines were quantified using Western blotting. Error bars represent the SD for each protein in individual cell groups from 3 separate experiments (B and D). Data were analyzed by 1-way ANOVA with Tukey’s multiple-comparison test (3 independent experiments). *P < 0.05, **P < 0.01, ***P < 0.005 vs. DMSO.