Effects of Lomerizine and Its Metabolite on Glioblastoma Cells

Glioblastoma is an incurable cancer with limited treatment options and a low survival rate. Temozolomide is the standard marketed small-molecule agent for glioblastoma therapy; therefore, we aimed to find new drugs among the marketed medicines for brain diseases because of their cerebral migratory p...

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Bibliographic Details
Published in:	Anticancer research Vol. 44; no. 7; p. 2943
Main Authors:	Uemichi, Yuki, Mabuchi, Miyuki, Tsuchiya, Natsumi, Yasuda, Seina, Nakao, Shuhei, Shimizu, Tadashi
Format:	Journal Article
Language:	English
Published:	Greece 01-07-2024
Subjects:	Apoptosis - drug effects Brain Neoplasms - drug therapy Brain Neoplasms - metabolism Brain Neoplasms - pathology Cell Line, Tumor Cell Proliferation - drug effects Dacarbazine - analogs & derivatives Dacarbazine - pharmacology Drug Resistance, Neoplasm - drug effects Glioblastoma - drug therapy Glioblastoma - metabolism Glioblastoma - pathology Humans Piperazines - pharmacology Temozolomide - pharmacology Lomerizine temozolomide anticancer drug glioblastoma metabolite
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Summary:	Glioblastoma is an incurable cancer with limited treatment options and a low survival rate. Temozolomide is the standard marketed small-molecule agent for glioblastoma therapy; therefore, we aimed to find new drugs among the marketed medicines for brain diseases because of their cerebral migratory property and found lomerizine, used for the treatment of migraine. We evaluated the effect of lomerizine and its metabolites against U251 glioblastoma cells and temozolomide-resistant cells, T98G and GB-1, caused by the expression of O(6)-methylguanine-DNA methyltransferase or P-glycoprotein, compared with temozolomide, and combined with it. The mechanism of action was investigated using inhibitors of necrosis or apoptosis. Lomerizine and its metabolite (M6) inhibited the proliferation of glioblastoma cells with greater potency and efficacy than temozolomide, including against temozolomide-resistant cells. The effects of lomerizine and M6 on glioblastoma were mainly attributed to the inhibition of proliferation because cells were not rescued by cell death inhibitors, such as necrosis or apoptosis inhibitors, although they were slightly rescued by necrostatin-1. Additionally, lomerizine and M6 combined with temozolomide were more effective at inhibiting the proliferation of U251 and GB-1 cells at some doses than single treatments. Lomerizine has been used for migraine treatment because of its brain-penetrating properties without serious side-effects; thus, it might potentially be expected to be used alone for glioblastoma, including temozolomide-resistant glioblastoma, or in combination with temozolomide.
ISSN:	1791-7530
DOI:	10.21873/anticanres.17106