A novel AKR1C3 inhibitor promotes ferroptosis susceptibility in glioblastoma cells

Glioblastoma multiforme (GBM) is one of the most aggressive malignancies in the central nervous system (CNS), mainly occurring in male adult patients. Despite the range of available treatment strategies, this tumour continues to carry a poor prognosis, largely due to therapy resistance and tumour recurrence, with a median survival ranging from 10 to 14 months. Therefore, evaluating new therapeutic strategies for eliminating cancer cells and limiting the survival of drug-resistant clones is crucial. In this context, induction of Ferroptosis could prove to be a new promising perspective. Ferroptosis has been recently discovered as a new type of programmed cell death which is characterised by the iron-dependent accumulation of lethal lipid peroxides that, through a series of mechanisms, can disrupt the redox balance of cancer cells. This type of cell death is studied as a new therapeutic strategy for many types of tumours since their deep dependence on redox homeostasis and their dysregulated iron metabolism make them possibly susceptible to Ferroptosis. In this thesis, using a novel synthesised AKR1C3 inhibitor, we evaluated AKR1C3 enzyme inhibition as a possible mechanism to enhance GBM cells' susceptibility towards ferroptosis induced by Ferroptosis Inducers (FINs). AKR1C3 indeed belongs to a large family of NADPH-dependent oxidoreductases, whose main aim is to reduce toxic aldehydes and ketone species to the corresponding primary and secondary alcohols. The combination of this new molecule with FINs resulted in a significant decrease in cell viability with respect to single treatments, as for increased lipid peroxidation and iron accumulation in cellular membranes, which are both hallmarks of ferroptosis. Additionally, the potential involvement of the autophagic pathway is evaluated. In conclusion, our findings offer novel evidence that GBM cells become more susceptible to ferroptosis induced by traditional FINs when AKR1C3 is pharmacologically inhibited, thus representing a new alternative pathway that could be exploited to overcome therapy resistance in GBM cells.