PTC596-Induced BMI-1 Inhibition Fights Neuroblastoma Multidrug Resistance by Inducing Ferroptosis

Neuroblastoma (NB) is a paediatric Cancer with noteworthy heterogeneity ranging from spontaneous regression to high-risk forms that are characterised by Cancer relapse and the acquisition of drug resistance. The most-used Anticancer drugs exert their cytotoxic effect by inducing oxidative stress, and long-term therapy has been demonstrated to cause chemoresistance by enhancing the antioxidant response of NB cells. Taking advantage of an in vitro model of multidrug-resistant (MDR) NB cells, characterised by high levels of glutathione (GSH), the overexpression of the oncoprotein BMI-1, and the presence of a mutant P53 protein, we investigated a new potential strategy to fight chemoresistance. Our results show that PTC596, an inhibitor of BMI-1, exerted a high cytotoxic effect on MDR NB cells, while PRIMA-1^MET, a compound able to reactivate mutant P53, had no effect on the viability of MDR cells. Furthermore, both PTC596 and PRIMA-1^MET markedly reduced the expression of epithelial-mesenchymal transition proteins and limited the clonogenic potential and the Cancer stemness of MDR cells. Of particular interest is the observation that PTC596, alone or in combination with PRIMA-1^MET and etoposide, significantly reduced GSH levels, increased peroxide production, stimulated lipid peroxidation, and induced Ferroptosis. Therefore, these findings suggest that PTC596, by inhibiting BMI-1 and triggering Ferroptosis, could be a promising approach to fight chemoresistance.

BMI-1; P53; ferroptosis; glutathione; multidrug resistance; neuroblastoma.