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PTC596-Induced BMI-1 Inhibition Fights Neuroblastoma Multidrug Resistance by Inducing Ferroptosis
Giulia Elda Valenti1, Antonella Roveri2, Rina Venerando2
1Department of Experimental Medicine, General Pathology Section, University of Genoa, 16132 Genoa, Italy.
Abstract:
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-1MET, a compound able to reactivate mutant P53, had no effect on the viability of MDR cells. Furthermore, both PTC596 and PRIMA-1MET 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-1MET 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.
Insights
This study explored a new strategy against multidrug-resistant neuroblastoma. PTC596, a BMI-1 inhibitor, effectively killed resistant cells and induced ferroptosis, offering a promising approach for chemoresistance.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Neuroblastoma (NB) exhibits significant heterogeneity, with high-risk forms often leading to relapse and drug resistance.
- Standard chemotherapy induces oxidative stress but can enhance antioxidant responses in NB cells, leading to chemoresistance.
- Multidrug-resistant (MDR) NB cells are characterized by high glutathione (GSH), BMI-1 overexpression, and mutant P53.
Purpose of the Study:
- To investigate a novel strategy to overcome chemoresistance in multidrug-resistant neuroblastoma cells.
- To evaluate the efficacy of BMI-1 inhibitor PTC596 and mutant P53 reactivator PRIMA-1MET in MDR NB models.
Main Methods:
- Utilized an in vitro model of multidrug-resistant (MDR) neuroblastoma (NB) cells.
- Assessed the cytotoxic effects of PTC596 and PRIMA-1MET on MDR NB cell viability.
- Analyzed the impact of these compounds on epithelial-mesenchymal transition (EMT) proteins, clonogenic potential, and cancer stemness.
- Measured GSH levels, peroxide production, lipid peroxidation, and induced ferroptosis.
Main Results:
- PTC596 demonstrated significant cytotoxicity against MDR NB cells, whereas PRIMA-1MET had no effect on cell viability.
- Both PTC596 and PRIMA-1MET reduced EMT protein expression, clonogenic potential, and cancer stemness in MDR cells.
- PTC596, alone or in combination, reduced GSH levels, increased peroxide and lipid peroxidation, and induced ferroptosis.
Conclusions:
- PTC596, by inhibiting BMI-1, shows promise in combating chemoresistance in neuroblastoma.
- Targeting BMI-1 and inducing ferroptosis represents a potential therapeutic strategy for drug-resistant neuroblastoma.
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