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 9

Effects of lomerizine treatment on cell signaling pathways in vivo.

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Effects of lomerizine treatment on cell signaling pathways in vivo. (A) ...
(A) Top panels: Representative immunohistochemical sections of the KGS01 mouse models showing phosphorylated STAT3 at tyrosine 705 and Ki-67 in untreated and human-dose lomerizine–treated brain tumors. Bar graph showing the percentage of p-STAT3 Y705–positive cells in each treatment group (left) and the immunoactivity of Ki-67 in each treatment group (right). Bottom panels: Representative immunohistochemical sections of the KGS10 mouse model showing phosphorylated STAT3 at tyrosine 705 and Ki-67 in untreated and human-dose lomerizine–treated brain tumors. Bar graph showing the percentage of p-STAT3 Y705–positive cells in each treatment group (left) and the immunoactivity of Ki-67 in each treatment group (right). (B) Representative immunohistochemical sections after TUNEL staining showing apoptotic cells. Inset indicating an enlarged image of cells undergoing apoptosis (stained black). Red arrows indicate the cells in the apoptotic state. Inset shows higher magnification image (4×) of apoptotic cell. Bar graph showing the number of apoptotic cells in each treatment group. (C) Schematic representation of the function of lomerizine in GICs and glioma cells. Bars represent mean values ± SD (A and B). Scale bars: 100 μm (A and B). Data were analyzed by 2-tailed Student’s t test. *P < 0.05, ***P < 0.005 vs. vehicle.