RESUMO
Glioma coined as a "butterfly" tumor associated with a dismal prognosis. Marine algal compounds with the richest sources of bioactive components act as significant anti-tumor therapeutics. However, there is a paucity of studies conducted on Fucoidan to enhance the anti-glioma efficacy of Temozolomide. Therefore, the present study aimed to evaluate the synergistic anti-proliferative, anti-inflammatory and pro-apoptotic effects of Fucoidan with Temozolomide in in vitro and in silico experimental setup. The anti-proliferative effects of Temozolomide and Fucoidan were evaluated on C6 glioma cells by MTT and migration assay. Modulation of inflammatory markers and apoptosis induction was affirmed at the morphological and transcriptional level by dual staining and gene expression. Molecular docking (MD) and molecular dynamics simulation (MDS) studies were performed against the targets to rationalize the inhibitory effect. The dual-drug combination significantly reduced the cell viability and migration of glioma cells in a synergistic dose-dependent manner. At the molecular level, the dual-drug combination significantly down-regulated inflammatory genes with a concomitant upregulation of pro-apoptotic marker. In consensus with our in vitro findings, molecular docking and simulation studies revealed that the anti-tumor ligands: Temozolomide, Fucoidan with 5-(3-Methy1-trizeno)-imidazole-4-carboxamide (MTIC), and 4-amino-5-imidazole-carboxamide (AIC) had the potency to bind to the inflammatory proteins at their active sites, mediated by H-bonds and other non-covalent interactions. The dual-drug combinatorial treatment synergistically inhibited the proliferation, migration of glioma cells and promoted apoptosis; conversely with the down-regulation of inflammatory genes. However, pre-clinical experimental evidence is warranted for the possible translation of this combination. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03814-6.
RESUMO
BACKGROUND: 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/ß-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/ß-catenin cascade using established genotoxic agents like temozolomide and pharmacological inhibitors would be an effective approach to modulate the Wnt/ß-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. OBJECTIVE: In this context, by employing computational tools, an attempt has been made to find out the novel combinations against the Wnt/ß-catenin signalling pathway. METHODS: 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/ß-catenin signalling. RESULTS: It was noted that all the experimental compounds showed profound interaction with two major receptors of the Wnt/ß-catenin pathway. CONCLUSION: 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/ß-catenin signalling in silico, and this will putatively open up new avenues for combination therapies in GBM treatment.
