Evaluation of Metformin as an anti-cancer agent in Medulloblastoma




Basha, Riyaz
Bowman, W. Paul
Sankpal, Umesh


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Evaluation of Metformin as an anti-cancer agent in Medulloblastoma Purpose: Medulloblastoma (MB) is the most common malignant brain tumor in children under 16 years of age. Standard treatment, including surgery, chemotherapy, and radiation, is successful for most; however, survivors often suffer from long-term neurocognitive and growth potential related sequelae. Therefore, there is a need to understand the molecular processes regulating MB growth to find less toxic therapies. Survivin is a protein in the Inhibitor of Apoptosis Protein (IAP) family that inhibits caspase activity. Survivin is highly expressed in MB and associated with a poor prognosis. Specificity protein 1 (Sp1) is a transcription factor regulating survivin expression and is overexpressed in many cancers. Interestingly, the use of Metformin (MET), an anti-diabetic drug, correlated with decreased occurrence of several cancers. Previous studies have demonstrated its anti-cancer activity in breast cancer cells as well. The objective of this study is to test the effect of MET on MB cells in vitro. Hypothesis: We hypothesize that MET treatment decreases the growth of MB cells in a dose and time-dependent manner, possibly inhibiting the expression of survivin via downregulating Sp1. Methods: DAOY (MB cell line from American Type Culture Collection) cells were treated with increasing concentrations of MET (0, 1, 5, 10, and 20 mM). Cell viability was assessed at 24 and 48 hours post-treatment using the CellTiter-Glo cell viability assay. Survivin and Sp1 expression in MET treated cells was determined by Western blot analysis. Potential mechanism of cell proliferation inhibition was investigated by measuring the induction of reactive oxygen species (ROS) through Flowcytometry. Results: MET treatment resulted in decreased cell viability in a dose and time dependent manner. MET treatment also decreased Sp1 and survivin expression indicating that the effect of MET is mediated via Sp1 transcription factor. We also observed MET induced cellular ROS formation, which could be a potential anti-cancer mechanism. Conclusion: Our data demonstrates that MET can inhibit MB cell growth, possibly via targeting Sp1 to down-regulate survivin and inducing ROS. We conclude that MET has the potential to be used in the treatment of MB. Due to limitations of using Metformin alone as an anti-cancer agent, additional experiments are underway to determine its use in conjunction with MB specific chemotherapeutic agents.


Research Appreciation Day Award Winner - 2018 Texas College of Osteopathic Medicine, Student Research Award - 1st Place
Research Appreciation Day Award Winner - 2018 Department of Pediatrics, Pediatric Research Award - 1st Place
Research Appreciation Day Award Winner - 2018 Medical Student Government Association - Best in Second Year Class