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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.

Glioblastoma multiforme (GBM) is one of the most common and malignant form of adult brain tumor with a high mortality rate and dismal prognosis. The present standard treatment comprising surgical resection followed by radiation and chemotherapy using temozolomide can broaden patient's survival to some extent. However, the advantages are not palliative due to the development of resistance to the drug and tumor recurrence following the multimodal treatment approaches due to both intra‐ and intertumoral heterogeneity of GBM. One of the major contributors to temozolomide resistance is O6‐methylguanine‐DNA methyltransferase. Furthermore, deficiency of mismatch repair, base excision repair, and cytoprotective autophagy adds to temozolomide obstruction. Rising proof additionally showed that a small population of cells displaying certain stem cell markers, known as glioma stem cells, adds on to the resistance and tumor progression. Collectively, these findings necessitate the discovery of novel therapeutic avenues for treating glioblastoma. As of late, after understanding the pathophysiology and biology of GBM, some novel therapeutic discoveries, such as drug repurposing, targeted molecules, immunotherapies, antimitotic therapies, and microRNAs, have been developed as new potential treatments for glioblastoma. To help illustrate, “what are the mechanisms of resistance to temozolomide” and “what kind of alternative therapeutics can be suggested” with this fatal disease, a detailed history of these has been discussed in this review article, all with a hope to develop an effective treatment strategy for GBM.

Aim: To study the synergistic anti-glioma efficacies of Temozolomide, Metformin and Epigallocatechin Gallate in U87MG and C6 glioma cells. Background: Glioblastoma (GBM) is the most malignant and invasive tumor of the central nervous system. The current standard treatment comprises surgical resection, followed by adjuvant radiotherapy and chemotherapy employing temozolomide (TMZ). Yet the survival rates for GBM patients is very low. Hence there is a need for new treatment regimes Objective: This study was aimed to unravel the synergistic anti-tumor potential of a biguanide drug, Metformin (MET) and a polyphenol, Epigallocatechin gallate (EGCG) to enhance the anti-GBM efficacy of the standard drug. Methods: Anti-proliferative effect of TMZ, MET and EGCG, individually and in combination was elucidated in U87MG (human) and C6 (rat) glioma cells using MTT assay and combination index was used to determine synergism. Cytotoxicity of the drugs was performed in HEK293T noncancerous cells. Apoptotic morphological changes in the cells were observed by AO/EtBr staining. Further, the effect of drugs on antioxidant and apoptotic genes (SOD, CAT, Nrf-2, Caspase-9 and Bcl-2) were evaluated using qRT-PCR and the protein levels of Nrf-2 and Caspase-9 was evaluated using ELISA. Results: The triple-drug combination (TMZ+ MET+ EGCG) synergistically inhibited the proliferation of U87MG and C6 glioma cells in a dose-dependent manner and promoted the apoptosis of glioma cells. The triple-drug combination significantly up-regulated the expression of antioxidant and apoptotic genes and induced oxidative stress suggesting a shift in equilibrium towards apoptosis. Conclusion: MET and EGCG in combination with TMZ synergistically promoted oxidative stress induced apoptosis in glioma cells. Hence, the combination of TMZ, MET and EGCG may be therapeutically exploited for improving the clinical outcomes of patients with GBM.