de Mello Renata Siqueira, Bento Carolina Adriane, de Oliveira Faria Rafael, Arnaud-Sampaio Vanessa Fernandes, Ulrich Henning, Miyagi Mariana Yasue Saito, de Araujo Gabriel Lima Barros, Lameu Claudiana
Biochemistry Department, Institute of Chemistry, University of Sao Paulo, Sao Paulo, Brazil.
Department of Pharmacy, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Purinergic Signal. 2025 Mar 13. doi: 10.1007/s11302-025-10078-7.
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 (IC approximately 300 times greater) compared to parental cells. P2Y receptor expression was augmented in vincristine-resistant cells, particularly after treatment with nanoFBZ and Brilliant Blue-G, while adenosine A1, A2B, and P2Y receptor expression levels decreased. P2X7 receptor expression was also reduced in vincristine-resistant cells treated with nanoFBZ. P2X7 receptor agonism and P2Y 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.
神经母细胞瘤是一种儿科肿瘤，约占儿童癌症的8%，与1至5岁儿童的高死亡率相关。标准治疗往往效果不佳，由于化疗耐药性的发展导致复发和转移。应对这一挑战的一种有前景的方法是靶向嘌呤能信号通路和药物重新利用。纳米制剂氟苯达唑和长春新碱的组合在ACN细胞中表现出协同作用，提高了治疗效果。长春新碱与P2X7受体拮抗剂亮蓝-G联合显示出拮抗作用，纳米氟苯达唑（nanoFBZ）与亮蓝-G之间的相互作用呈剂量依赖性。此外，每周用213 nM长春新碱处理ACN细胞三周，产生了长春新碱耐药细胞，其耐药性（IC约高300倍）明显高于亲代细胞。P2Y受体表达在长春新碱耐药细胞中增加，特别是在用纳米氟苯达唑和亮蓝-G处理后，而腺苷A1、A2B和P2Y受体表达水平下降。在用纳米氟苯达唑处理的长春新碱耐药细胞中，P2X7受体表达也降低。P2X7受体激动和P2Y受体阻断略微提高了耐药性。总之，本研究表明，将纳米氟苯达唑与长春新碱化疗联合使用可能为提高神经母细胞瘤的治疗效果提供一种有前景的策略。纳米氟苯达唑与长春新碱之间的协同作用增强了治疗效果，P2X7受体拮抗进一步降低了神经母细胞瘤细胞的活力。
