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Glioblastoma Multiforme (GBM) is classified as a malignant grade IV astrocytoma, and is considered to be the most biologically aggressive brain tumour with a 5-year survival rate of ~4%. The most frequent issue arising with GBM tumours is the high level of resistance observed to conventional therapeutic methods i.e. surgery, chemotherapy and radiation, thus signifying the urgency for the development of novel therapeutic methods. This study aims to investigate and develop both a complimentary and novel method to overcome the current treatment barriers. We have investigated the use of novel technologies such as cold atmospheric plasma (CAP) as an alternative to radiotherapy. Employing methods such as cytotoxicity assays, molecular inhibitors, confocal microscopy and flow cytometry, for the first time, we report that CAP induces a ROS, JNK and Caspase independent mechanism of cell death in the GBM cells that can be greatly enhanced when used in combination with low doses of TMZ. We have also further elucidated that CAP results in the activation of autophagy prior to cell death. Current chemotherapeutics used for the treatment of GBM have offered little progression in the reduction of years of life lost. We have investigated the efficacy of naturally available bioactive compound Ursolic acid (UA) as a potential alternative to current chemotherapeutics. Using migratory assays, cytotoxicity assay, confocal microscopy and flow cytometry we have identified that UA activates autophagy prior to JNK dependent mechanism of cell death. A significant issue with GBM is its ability to spread and infiltrate throughout normal brain tissue. We demonstrated that UA successfully inhibits GBM cell migration through a JNK independent mechanism, more effectively than the current chemotherapeutics. It is evident that there are inconsistencies in the literature regarding the mechanism of cell death which occurs in GBM cells through critical analysis of the literature and multiple independent treatment modalities, and following the guidelines set out by the national cell death committee, we have demonstrated that U373MG GBM cells result in activation of the autophagy following treatment prior to the cells demise.
Conway, G. (2016) Novel Therapeutic Approaches to Induce Autophagy in Brain Cancer. Doctoral thesis submitted to Technological University Dublin, 2016. doi:10.21427/D7632V