Effects of nanoflubendazole and purinergic signaling modulation in overcoming neuroblastoma chemoresistance.

Abstract

Neuroblastoma is a pediatric tumor accounting for approximately 8% of childhood cancers and is associated with high mortality rates among children aged 1 to 5 years. Standard treatments often fall short, leading to recurrence and metastasis due to the development of chemoresistance. A promising approach to address this challenge involves targeting purinergic signaling pathways and drug repurposing. The combination of flubendazole in nanoformulation and vincristine exhibited synergistic effects in ACN cells, enhancing treatment efficacy. Vincristine combined with the P2X7 receptor antagonist Brilliant Blue-G showed antagonistic effects, and interactions between nanoFBZ and Brilliant Blue-G were dose-dependent. Furthermore, ACN cells exposed to 213 nM of vincristine weekly for three weeks resulted in vincristine-resistant cells with significantly higher resistance (IC₅₀ approximately 300 times greater) compared to parental cells. P2Y₂ receptor expression was augmented in vincristine-resistant cells, particularly after treatment with nanoFBZ and Brilliant Blue-G, while adenosine A1, A2B, and P2Y₆ receptor expression levels decreased. P2X7 receptor expression was also reduced in vincristine-resistant cells treated with nanoFBZ. P2X7 receptor agonism and P2Y₂ receptor blockade slightly elevated resistance. In conclusion, this study suggests that combining nanoFBZ with vincristine chemotherapy may offer a promising strategy for improving the treatment efficacy of neuroblastoma. The synergy between nanoFBZ and vincristine enhanced therapeutic outcomes, and P2X7 receptor antagonism further reduced neuroblastoma cell viability.