Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Święcicki 4 Str., 60-781 Poznań, Poland.
Department of Pharmacognosy, Poznan University of Medical Sciences, Rokietnicka 3 Str., 60-806 Poznań, Poland.
Cells. 2022 Mar 23;11(7):1084. doi: 10.3390/cells11071084.
Lichens are a source of secondary metabolites with significant pharmacological potential. Data regarding their possible application in glioblastoma (GBM) treatment are, however, scarce. The study aimed at analyzing the mechanism of action of six lichen secondary metabolites: atranorin, caperatic acid, physodic acid, squamatic acid, salazinic acid, and lecanoric acid using two- and three-dimensional GBM cell line models. The parallel artificial membrane permeation assay was used to predict the blood-brain barrier penetration ability of the tested compounds. Their cytotoxicity was analyzed using the MTT test on A-172, T98G, and U-138 MG cells. Flow cytometry was applied to the analysis of oxidative stress, cell cycle distribution, and apoptosis, whereas qPCR and microarrays detected the induced transcriptomic changes. Our data confirm the ability of lichen secondary metabolites to cross the blood-brain barrier and exert cytotoxicity against GBM cells. Moreover, the compounds generated oxidative stress, interfered with the cell cycle, and induced apoptosis in T98G cells. They also inhibited the Wnt/β-catenin pathway, and this effect was even stronger in case of a co-treatment with temozolomide. Transcriptomic changes in cancer related genes induced by caperatic acid and temozolomide were the most pronounced. Lichen secondary metabolites, caperatic acid in particular, should be further analyzed as potential anti-GBM agents.
地衣是具有重要药理潜力的次生代谢物的来源。然而，关于它们在胶质母细胞瘤（GBM）治疗中可能应用的数据却很少。本研究旨在分析六种地衣次生代谢物：变形菌素、海角酸、地衣酚酸、鳞毛蕨酸、水杨酰苯甲酸和栓菌酸的作用机制，使用二维和三维 GBM 细胞系模型进行分析。平行人工膜渗透测定法用于预测测试化合物的血脑屏障穿透能力。使用 MTT 试验在 A-172、T98G 和 U-138 MG 细胞上分析它们的细胞毒性。流式细胞术用于分析氧化应激、细胞周期分布和细胞凋亡，而 qPCR 和微阵列检测诱导的转录组变化。我们的数据证实了地衣次生代谢物能够穿过血脑屏障并对 GBM 细胞产生细胞毒性。此外，这些化合物在 T98G 细胞中产生氧化应激、干扰细胞周期并诱导细胞凋亡。它们还抑制了 Wnt/β-catenin 通路，而与替莫唑胺联合治疗时，这种作用甚至更强。海角酸和替莫唑胺诱导的癌症相关基因的转录组变化最为明显。地衣次生代谢物，特别是海角酸，应作为潜在的抗 GBM 药物进一步分析。
