School of Pharmacy, Hyogo Medical University, Kobe, Japan.
School of Pharmacy, Hyogo Medical University, Kobe, Japan
Anticancer Res. 2024 Jul;44(7):2943-2952. doi: 10.21873/anticanres.17106.
BACKGROUND/AIM: 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.
背景/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。替莫唑胺是胶质母细胞瘤治疗的标准上市小分子药物；因此，我们旨在从上市的脑部疾病药物中寻找新的药物，因为它们具有脑迁移特性，并发现了用于治疗偏头痛的洛美利嗪。
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 T98G 和 GB-1 替莫唑胺耐药细胞的影响，这些细胞通过表达 O(6)-甲基鸟嘌呤-DNA 甲基转移酶或 P-糖蛋白引起，与替莫唑胺进行比较，并与它联合使用。使用坏死或凋亡抑制剂研究作用机制。
洛美利嗪及其代谢物（M6）对胶质母细胞瘤细胞的增殖具有比替莫唑胺更强的效力和功效，包括对替莫唑胺耐药细胞。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，如坏死或凋亡抑制剂，不能挽救细胞，尽管它们被坏死蛋白抑制剂-1 轻微挽救。此外，与单独治疗相比，洛美利嗪和 M6 联合替莫唑胺在某些剂量下更有效地抑制 U251 和 GB-1 细胞的增殖。
洛美利嗪因其具有穿透大脑的特性且没有严重的副作用而被用于偏头痛的治疗；因此，它可能有望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。
