Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
目的：胶质母细胞瘤是一种无法治愈的癌症，治疗选择有限，生存率低。替莫唑胺是用于胶质母细胞瘤治疗的标准市售小分子药物；因此，由于其脑迁移特性，我们旨在在市售的治疗脑疾病的药物中寻找新药，并发现了洛美利嗪，用于治疗偏头痛。
方法：我们评估了洛美利嗪及其代谢物对U251胶质母细胞瘤细胞和替莫唑胺耐药细胞的作用，由O（6）-甲基鸟嘌呤-DNA甲基转移酶或P-糖蛋白的表达引起的T98G和GB-1，与替莫唑胺相比，并与之结合。使用坏死或凋亡抑制剂研究了作用机理。
结果：洛美利嗪及其代谢产物（M6）比替莫唑胺抑制胶质母细胞瘤细胞增殖的效力和效力更大，包括对抗替莫唑胺抗性细胞。洛美利嗪和M6对胶质母细胞瘤的作用主要归因于抑制增殖，因为细胞死亡抑制剂无法挽救细胞，如坏死或凋亡抑制剂，尽管它们被坏死抑制素-1稍微拯救。此外,洛美利嗪和M6联合替莫唑胺在某些剂量下比单一治疗更有效地抑制U251和GB-1细胞的增殖。
结论：洛美利嗪因其具有脑穿透性而没有严重副作用而被用于偏头痛的治疗；因此，它可能会被单独用于胶质母细胞瘤，包括替莫唑胺耐药的胶质母细胞瘤，或与替莫唑胺联合使用。
方法：我们评估了洛美利嗪及其代谢物对U251胶质母细胞瘤细胞和替莫唑胺耐药细胞的作用，由O（6）-甲基鸟嘌呤-DNA甲基转移酶或P-糖蛋白的表达引起的T98G和GB-1，与替莫唑胺相比，并与之结合。使用坏死或凋亡抑制剂研究了作用机理。
结果：洛美利嗪及其代谢产物（M6）比替莫唑胺抑制胶质母细胞瘤细胞增殖的效力和效力更大，包括对抗替莫唑胺抗性细胞。洛美利嗪和M6对胶质母细胞瘤的作用主要归因于抑制增殖，因为细胞死亡抑制剂无法挽救细胞，如坏死或凋亡抑制剂，尽管它们被坏死抑制素-1稍微拯救。此外,洛美利嗪和M6联合替莫唑胺在某些剂量下比单一治疗更有效地抑制U251和GB-1细胞的增殖。
结论：洛美利嗪因其具有脑穿透性而没有严重副作用而被用于偏头痛的治疗；因此，它可能会被单独用于胶质母细胞瘤，包括替莫唑胺耐药的胶质母细胞瘤，或与替莫唑胺联合使用。
