Wnt/β-catenin Antagonists: Exploring New Avenues to Trigger Old Drugs in Alleviating Glioblastoma Multiforme

Abstract

Background: Glioblastoma multiforme is one of the most heterogenous primary brain tumor with high mortality. Nevertheless, of the current therapeutic approaches, survival rate remains poor with 12 to 15 months following preliminary diagnosis, this warrants the need for effective treatment modality. Wnt/β-catenin pathway is presumably the most noteworthy pathway up-regulated in almost 80% GBM cases contributing to tumor-initiation, progression and survival. Therefore, therapeutic strategies targeting key components of Wnt/β-catenin cascade using established genotoxic agents like temozolomide and pharmacological inhibitors would be an effective approach to modulate 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 chemo-resistance in GBM. Objective: In this context, by employing computational tools, an attempt has been carried out to speculate the novel combinations against Wnt/β-catenin signaling pathway. Methods: We have explored the binding interactions of three conventional drugs namely temozolomide, metformin, chloroquine along with three natural compounds viz., epigallocatechin gallate, naringenin and phloroglucinol on the major receptors of Wnt/β-catenin signaling. Results: It was noted that all the experimental compounds possessed profound interaction with the two major receptors of Wnt/β-catenin pathway. Conclusion: To the best of our knowledge, this study is the first of its kind to characterize the combined interactions of the afore-mentioned drugs on Wnt/β-catenin signaling in silico and this will putatively open up new avenues for combination therapies in GBM treatment.

A combination of Metformin and Epigallocatechin Gallate Potentiates Glioma Chemotherapyin vivo

“…However, the regulation of ROS is often known to maintain cellular stability and enhance tumor progression by modulating various proliferative pathways such as PI3K/AKT/mTOR pathway, MAPK pathway and Wnt signalling pathway (Precilla et al, 2021). Among these, the PI3K/AKT/mTOR pathway has been reported to be aberrantly activated in almost 80% glioma cases (Cancer Genome Atlas Research Network, 2008;Cheng et al, 2009).…”

“…In highly proliferative tumors such as glioma, the increased metabolic rates lead to the accumulation of higher concentration of free radicals, leading to an increase in ROS levels (Olivier et al, 2020). However, the regulation of ROS is often known to maintain cellular stability and enhance tumor progression by modulating various proliferative pathways such as PI3K/AKT/mTOR pathway, MAPK pathway and Wnt signalling pathway (Precilla et al, 2021). Among these, the PI3K/AKT/mTOR pathway has been reported to be aberrantly activated in almost 80% glioma cases (Cancer Genome Atlas Research Network, 2008; Cheng et al, 2009).…”

Dynamics of repurposing synthetic and natural compounds against WNT/β-Catenin signaling in glioma- Anin vivoapproach

“…The copyright holder for this preprint this version posted December 3, 2022. ; https://doi.org/10.1101/2022.12.02.518940 doi: bioRxiv preprint Interestingly, from our preliminary in silico analysis, we had observed that all the four drugs namely, TMZ, CHL, NAR and PGL had depicted a profound interaction with two major receptors of WNT/β-catenin signaling pathway namely, Frizzled (FZD) and the co-receptor, the low-density lipoprotein receptor-related protein/alpha 2-macroglobulin receptors (LRP5/6) (Precilla et al 2021). On grounds of this in silico finding, we analysed the regulation of WNT/β-catenin pathway by this quadruple-drug cocktail (TCNP) with major focus on the expression signatures of the main components namely, EGFR, β-catenin, c-myc, c-jun and ERK-2.…”

“…However, besides observation of their pathological effect, studies that shed molecular insights on the mechanism of action of the drugs would lay a profound background for further investigations on this quadruple-drug combination (TCNP). This is because, being a tumor with complex heterogeneity, GB is characterized by aberrant activation of major signal transduction pathways such as PI3K/AKT/mTOR, RAS/RAF/MAPK, Notch, Hedgehog and WNT signalling pathways which contributes to glioma proliferation (Jeuken et al 2007; Fan and Weiss 2010; Stockhausen et al 2010; Liu et al 2011, 2014; Precilla et al 2021; Daisy Precilla et al 2022). Among these, the WNT/ β-catenin signalling pathway is of paramount importance in gliomagenesis, as it enables GB cells to recapitulate the embryonic processes, thereby promoting glioma growth, progression and therapeutic resistance (Latour et al 2021).…”

“…Interestingly, from our preliminary in silico analysis, we had observed that all the four drugs namely, TMZ, CHL, NAR and PGL had depicted a profound interaction with two major receptors of WNT/β-catenin signaling pathway namely, Frizzled (FZD) and the co-receptor, the low-density lipoprotein receptor-related protein/alpha 2-macroglobulin receptors (LRP5/6) (Precilla et al 2021). On grounds of this in silico finding, we analysed the Further, as a stepping stone to streamline the down-stream events being modulated following the suppression of WNT/β-catenin signaling, we then studied the expression profiles of the key drivers of apoptosis.…”