16th Annual Child Health Research Days

Thank you for joining us (virtually!|

Save the date: Oct. 6 & 7, 2021

Abstracts

#62 Anti-cancer Effects of Mevalonate-Cascade Inhibition in Medulloblastoma Brain Tumor as a Novel and Non-Classical Therapeutic Approach


Annan Ali Sher, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba; Kimia Sheikholeslami, University of Toronto; Daniel Kroft, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba; Sandhini Lockman, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba; Shahla Shojaei, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba; Saeid Ghawami, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba; Mojgan Rastegar, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba


Introduction

Medulloblastoma is the most common pediatric malignant brain tumor. Recently it has been reported that cholesterol metabolism pathway is involved in medulloblastoma, and 3-hydroxy-3-methyl-glutaryl-coenzyme-A-reductase (HMG-CoA reductase) is considered an oncogene. We examined the anti-cancer effects of a mevalonate cascade inhibitor on the proliferation of aggressive and non-aggressive models of human medulloblastoma using three different cell lines and the molecular mechanisms of action of this drug on cell survival.


Methods

Initially, we studied the dose-dependent properties of mevalonate-cascade inhibitor by MTT assays at 24hrs, 48hrs, 72hrs and 96hrs. Subsequently, we used mevalonate, farnesyl pyrophosphate, geranygeranyl pyrophosphate and cholesterol in presence of mevalonate cascade inhibitor. Propidium iodide-based flow cytometry apoptosis assay and luminescence caspase Glu assay (caspase-3/-7, -9, -8) was used to investigate apoptosis involvement in this drug induced cell death. Further experiments (western blots) are in progress to confirm and investigate the regulation of apoptosis via cross-talk of apoptosis and autophagy in these cell lines induced by this drug.


Results

Our results indicated that mevalonate-cascade inhibition is effective in all tested cell lines, particularly against Daoy cells causing significant cell death (P-value of 0.0533 for 0.5uM drug concentration after 96 hrs). Our rescue experiments highlighted the possible involvement of small Rho-GTPase in the regulation of mevalonate cascade inhibition-induced apoptosis in meduloblastoma cells. Our results also showed a drastic increase in Caspase activities in all three cell lines (P value < 0.0001), while specificity of the involved caspases were different among different types of meduloblastoma cells.


Conclusion

Our studies suggest an effective potential non-classical therapeutic avenue for medulloblastoma as to the best of our knowledge; selective anti-proliferative role of this drug has not been tested on medulloblastoma.