Glioblastoma (GBM) is a common and aggressive brain tumor with a median survival of 12–15 months. Temozolomide (TMZ) is a first-line chemotherapeutic agent used in GBM therapy, but the occurrence of drug resistance limits its antitumor activity. The natural compound cedrol has remarkable antitumor activity and is derived from Cedrus atlantica. In this study, we investigated the combined effect of TMZ and cedrol in GBM cells in vitro and in vivo. The TMZ and cedrol combination treatment resulted in consistently higher suppression of cell proliferation via regulation of the AKT and MAPK signaling pathways in GBM cells. The combination treatment induced cell cycle arrest, cell apoptosis, and DNA damage better than either drug alone. Furthermore, cedrol reduced the expression of proteins associated with drug resistance, including O⁶-methlyguanine-DNA-methyltransferase (MGMT), multidrug resistance protein 1 (MDR1), and CD133 in TMZ-treated GBM cells. In the animal study, the combination treatment significantly suppressed tumor growth through the induction of cell apoptosis and decreased TMZ drug resistance. Moreover, cedrol-treated mice exhibited no significant differences in body weight and improved TMZ-induced liver damage. These results imply that cedrol may be a potential novel agent for combination treatment with TMZ for GBM therapy that deserves further investigation.

中文翻译：

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Cedrol 是一种倍半萜醇，通过调节 DNA 损伤反应和 MGMT 表达增强替莫唑胺在减弱耐药性方面的抗癌功效。

胶质母细胞瘤 (GBM) 是一种常见的侵袭性脑肿瘤，中位生存期为 12-15 个月。替莫唑胺（TMZ）是用于GBM治疗的一线化疗药物，但耐药性的出现限制了其抗肿瘤活性。源自大西洋雪松的天然复合雪松具有显着的抗肿瘤活性. 在这项研究中，我们研究了 TMZ 和雪松酚在体外和体内对 GBM 细胞的联合作用。TMZ 和雪松醇联合治疗通过调节 GBM 细胞中的 AKT 和 MAPK 信号通路导致对细胞增殖的持续更高的抑制。联合治疗比单独使用任一种药物更好地诱导细胞周期停滞、细胞凋亡和 DNA 损伤。此外，雪松降低了与耐药性相关的蛋白质的表达，包括O ⁶-甲基鸟嘌呤-DNA-甲基转移酶 (MGMT)、多药耐药蛋白 1 (MDR1) 和 TMZ 处理的 GBM 细胞中的 CD133。在动物研究中，联合治疗通过诱导细胞凋亡和降低 TMZ 耐药性显着抑制了肿瘤生长。此外，雪松醇治疗的小鼠在体重和 TMZ 诱导的肝损伤方面没有表现出显着差异。这些结果意味着雪松醇可能是一种潜在的新型药物，可与 TMZ 联合治疗 GBM，值得进一步研究。