Central Inter-Disciplinary Research Facility, School of Biological Sciences, Sri Balaji Vidyapeeth (Deemed-to-be University), Puducherry, India.
Department of Pharmacy, National University of Singapore, Singapore.
Curr Mol Pharmacol. 2022;15(2):338-360. doi: 10.2174/1874467214666210420115431.
Glioblastoma Multiforme (GBM) is one of the most heterogeneous primary brain tumors with high mortality. In spite of the current therapeutic approaches, the survival rate remains poor, with death occurring within 12 to 15 months after the preliminary diagnosis. This warrants the need for an effective treatment modality. The Wnt/β-catenin pathway is presumably the most noteworthy pathway upregulated in almost 80% of GBM cases, contributing to tumor initiation, progression, and survival. Therefore, therapeutic strategies targeting key components of the Wnt/β-catenin cascade using established genotoxic agents like temozolomide and pharmacological inhibitors would be an effective approach to modulate the Wnt/β-catenin pathway. Recently, drug repurposing by means of effective combination therapy has gained importance in various solid tumors, including GBM, by targeting two or more proteins in a single pathway, thereby possessing the ability to overcome the hurdle implicated by chemoresistance in GBM.
In this context, by employing computational tools, an attempt has been made to find out the novel combinations against the Wnt/β-catenin signalling pathway.
We have explored the binding interactions of three conventional drugs - namely temozolomide, metformin and chloroquine - along with three natural compounds, viz. epigallocatechin gallate, naringenin and phloroglucinol, on the major receptors of Wnt/β-catenin signalling.
It was noted that all the experimental compounds showed profound interaction with two major receptors of the Wnt/β-catenin pathway.
To the best of our knowledge, this study is the first of its kind to characterize the combined interactions of the aforementioned drugs with the Wnt/β-catenin signalling in silico, and this will putatively open up new avenues for combination therapies in GBM treatment.
多形性胶质母细胞瘤（GBM）是一种最具异质性的原发性脑肿瘤，死亡率极高。尽管目前有多种治疗方法，但生存率仍然很差，初步诊断后 12 至 15 个月内就会死亡。因此，需要寻找一种有效的治疗方法。Wnt/β-连环蛋白途径可能是在近 80%的 GBM 病例中上调最显著的途径之一，有助于肿瘤的起始、进展和存活。因此，使用已建立的遗传毒性药物（如替莫唑胺）和药理学抑制剂靶向 Wnt/β-连环蛋白级联的关键成分的治疗策略将是调节 Wnt/β-连环蛋白途径的有效方法。最近，通过有效的联合治疗进行药物再利用在包括 GBM 在内的各种实体瘤中变得越来越重要，通过在单个途径中靶向两种或更多种蛋白质，从而具有克服 GBM 中化疗耐药性所带来的障碍的能力。
在这种情况下，我们通过使用计算工具，试图找出针对 Wnt/β-连环蛋白信号通路的新的联合药物。
我们探索了三种常规药物——替莫唑胺、二甲双胍和氯喹——以及三种天然化合物——表没食子儿茶素没食子酸酯、柚皮苷和间苯三酚——与 Wnt/β-连环蛋白信号的主要受体的结合相互作用。
研究发现，所有实验化合物均与 Wnt/β-连环蛋白途径的两个主要受体表现出显著的相互作用。
据我们所知，这项研究是首次在体内对上述药物与 Wnt/β-连环蛋白信号的联合相互作用进行特征描述，这将为 GBM 治疗中的联合治疗开辟新的途径。
