Cell & Molecular Biology

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/32541


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    Investigating the mechanism of action of metformin and tolfenamic acid in medulloblastoma cells
    (2024-03-21) Sharna, Ansley; Mata, Fernanda; Sankpal, Umesh
    Purpose: Medulloblastoma, a highly malignant CNS tumor primarily diagnosed in children, presents a complex challenge in the field of medicine. While current multimodal treatment approaches, including total excision, chemotherapy, and radiation, yield relatively high survival rates, they are often accompanied by a range of significant adverse effects in adulthood, including neurological and motor deficits, endocrine dysfunction, hearing loss, and secondary tumors. Thus, more recent studies have shifted their focus to developing alternative, more precisely targeted anti-tumor therapies to mitigate the toxicity associated with existing therapies and enhance patient quality of life. An approach to address this problem involves investigating the synergistic potential of drug combination therapy using FDA-approved drugs to treat medulloblastoma. Among the drugs being investigated are Metformin (Met), an antidiabetic medication, and Tolfenamic Acid (TA), a nonsteroidal anti-inflammatory drug (NSAID) used for migraine treatment. Both drugs have been shown to exhibit anti-cancer activity. Previous work conducted in our laboratory has provided evidence of TA’s anticancer activity being mediated through the downregulation of pro-cancer Sp1 and survivin protein expression. The objective of this study was to enhance understanding of the mechanisms of action of metformin and tolfenamic acid by assessing their cell cycle-associated effects on DAOY human medulloblastoma cancer cells using Western blotting and flow cytometry techniques. Methods: The efficacies of Met and TA in terms of their anticancer effects were evaluated by determining the IC50 values of each drug using CellTiter-Glo and CCK-8 cell viability assays. The cell cycle effects of TA and Met were studied by Western blot analysis using protein extracts from treated DAOY cells. In addition, a cell cycle analysis of treated cells was performed using flow cytometry. Results: In our studies, both TA and Met were found to demonstrate anti-proliferative effects on DAOY cells. As demonstrated by Western blotting and flow cytometry analysis, the antiproliferative effects of both TA and Met were mediated through cell cycle arrest. Conclusion: This study suggests the significant potential of utilizing Met and TA in novel drug combination therapy for medulloblastoma. Their effects on protein expression open possibilities for enhancing cell cycle arrest or inducing apoptosis while decreasing the use of toxic therapies. Given the importance of minimizing long-term effects in children being treated for medulloblastoma and enhancing their quality of life, the mechanisms of Tolfenamic Acid and Metformin can be further explored.