Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Department of Rehabilitation, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Neurochem Int. 2022 Jul;157:105348. doi: 10.1016/j.neuint.2022.105348. Epub 2022 Apr 29.
Temozolomide (TMZ) is generally applied for glioma treatment, while drug resistance of TMZ limits its therapeutic efficacy. Mannose exerts evident anti-tumor effect. We intended to investigate whether mannose enhanced TMZ sensitivity to glioma and examined the underlying mechanism.
MTT and clone formation assays were performed to detect cell viability and proliferation. Cell apoptosis was measured by flow cytometry. The protein and gene expression levels were detected by Western blot and qRT-PCR assays. Xenograft glioma model was established to explore the influence of mannose in vivo.
Mannose inhibited glioma cell growth, which was facilitated by knockdown of phosphomannose isomerase (PMI) while reversed by overexpression of PMI. Mannose enhanced the sensitivity of glioma cells to TMZ, indicated by the further inhibited cell viability and colony formation and the aggravated cell apoptosis, which was reversed by overexpression of O6-methylguanine DNA methyltransferase (MGMT). Furthermore, mannose and TMZ inhibited MGMT expression and Wnt/β-catenin activation. Moreover, activating Wnt/β-catenin pathway blocked anti-proliferative effect induced by mannose and TMZ, which was further suppressed by overexpressed MGMT. Mannose inhibited glioma growth, suppressed Ki67 and downregulated MGMT and β-catenin in vivo.
Mannose inhibited MGMT to enhance sensitivity of glioma cells to TMZ, with Wnt/β-catenin pathway involvement. Our data suggested that mannose could be an innovative agent to improve glioma treatment, particularly in TMZ-resistant glioma with high MGMT.
替莫唑胺（TMZ）通常用于治疗脑胶质瘤，但 TMZ 的耐药性限制了其治疗效果。甘露糖具有明显的抗肿瘤作用。本研究旨在探讨甘露糖是否能增强 TMZ 对脑胶质瘤的敏感性，并探讨其潜在机制。
采用 MTT 和集落形成实验检测细胞活力和增殖，流式细胞术检测细胞凋亡，Western blot 和 qRT-PCR 检测蛋白和基因表达水平。建立异种移植脑胶质瘤模型，探讨甘露糖在体内的影响。
甘露糖抑制脑胶质瘤细胞生长，磷酸甘露糖异构酶（PMI）敲低可促进，PMI 过表达则逆转。甘露糖增强了脑胶质瘤细胞对 TMZ 的敏感性，表现为细胞活力和集落形成进一步抑制，细胞凋亡加剧，而过表达 O6-甲基鸟嘌呤 DNA 甲基转移酶（MGMT）则逆转了这一作用。此外，甘露糖和 TMZ 抑制 MGMT 表达和 Wnt/β-catenin 激活。此外，激活 Wnt/β-catenin 通路可阻断甘露糖和 TMZ 诱导的增殖抑制作用，而过表达 MGMT 则进一步抑制该作用。甘露糖抑制脑胶质瘤生长，抑制 Ki67，下调 MGMT 和β-catenin 表达。
甘露糖通过抑制 MGMT 增强脑胶质瘤细胞对 TMZ 的敏感性，涉及 Wnt/β-catenin 通路。我们的数据表明，甘露糖可能是一种创新药物，可改善脑胶质瘤的治疗效果，特别是在 MGMT 高表达的 TMZ 耐药性脑胶质瘤中。
