Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
Universidad Autónoma de Nuevo León, Centro de Investigación Y Desarrollo en Ciencias de La Salud, Monterrey, Nuevo Leon, Mexico.
Invest New Drugs. 2022 Jun;40(3):565-575. doi: 10.1007/s10637-022-01233-7. Epub 2022 Mar 21.
Glioblastoma multiforme (GBM) is a malignant CNS tumor with a poor prognosis. GBM shows aberrant glycosylation with hypersialylation. This property is a potential target for therapy. This study investigates the growth inhibitory efficacy of poly-guanidine (GuaDex), with an affinity for sialic acid (Sia). Glioma cell cultures and patient-derived glioma cell lines (PDGCLs) expressing Prominin-1 (CD133) were used. Human fibroblasts and astrocyte-derived cells were used as controls. Temozolomide (standard GBM drug, TMZ) and DMSO were used as a comparison. GuaDex at 1-10 µM concentrations, were incubated for 3.5-72 h and with PDGCLs cells for 6-24 h. The cytotoxicity was estimated with a fluorometric cytotoxicity assay (FMCA). Fluorescence-labelled GuaDex was used to study the cell interactions. Sia expression was confirmed with a fluorescence labelled Sia binding lectin. Expression of glial fibrillary acidic protein was determined. GuaDex induction of growth inhibition was fast, showing after less than 5 min incubation while the control cells were not affected even after 50 min incubation. The growth inhibitory effect on PDGCLs spheroids was persistent still showing after 4 weeks post-treatment. The growth inhibition of GuaDex was induced at low µM concentrations while TMZ induced only a slight inhibition at mM concentrations. GuaDex efficacy appears significant and warrants further studies.
多形性胶质母细胞瘤（GBM）是一种预后不良的中枢神经系统恶性肿瘤。GBM 表现出异常的糖基化，即过度唾液酸化。这种特性是治疗的潜在靶点。本研究探讨了聚胍（GuaDex）对表达 Prominin-1（CD133）的神经胶质瘤细胞培养物和患者来源的神经胶质瘤细胞系（PDGCLs）的生长抑制作用。使用人成纤维细胞和星形胶质细胞衍生细胞作为对照。替莫唑胺（标准 GBM 药物，TMZ）和 DMSO 用作比较。将 GuaDex 以 1-10 μM 的浓度孵育 3.5-72 h，并与 PDGCLs 细胞孵育 6-24 h。使用荧光细胞毒性测定法（FMCA）估计细胞毒性。使用荧光标记的 GuaDex 研究细胞相互作用。用荧光标记的 Sia 结合凝集素确认 Sia 表达。确定神经胶质纤维酸性蛋白的表达。GuaDex 诱导的生长抑制作用迅速，孵育不到 5 分钟即可显示，而对照细胞即使孵育 50 分钟也不受影响。即使在治疗后 4 周，PDGCLs 球体的生长抑制作用仍然持续。GuaDex 在低 μM 浓度下诱导生长抑制，而 TMZ 仅在 mM 浓度下诱导轻微抑制。GuaDex 的疗效似乎显著，值得进一步研究。
