Neuroblastoma (NB) is the common pediatric tumor of the sympathetic nervous system characterized by poor prognosis. Owing to the challenges such as high tumor heterogeneity, multidrug resistance, minimal residual disease, etc., there is an immediate need for exploring new therapeutic strategies and effective treatments for NB. Herein, in the current study, we explored the unexplored response of NB cells to the second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585(JNJ) and the lysosomotropic agent, Chloroquine (CQ) alone and upon JNJ/CQ treatment as a plausible therapeutic. We identify that while JNJ alone induced autophagy in NB cells, JNJ/CQ treatment decreased the viability and proliferation of NB cells in vitro by switching from autophagy to apoptosis. Further we found that autophagy inhibition by CQ pre-treatment led to the generation of ROS and a decrease in the mitochondrial membrane potential (MMP) that subsequently caused caspase-3-mediated apoptotic cell death in NB cells. Corroborating the above observations, we found that the ROS scavenger N-acetylcysteine (NAC) countered caspase-3 activity and the cells were rescued from apoptosis. Finally, these observations establish that JNJ/CQ treatment resulted in cell death in NB cells by triggering the formation of ROS and disruption of MMP, suggesting that modulation of JNJ-induced autophagy by CQ represents a promising new therapeutic approach in NB.

中文翻译：

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抑制JNJ-26481585介导的自噬通过神经母细胞瘤细胞中的ROS激活和线粒体膜电位破坏而诱导凋亡。

神经母细胞瘤（NB）是交感神经系统的常见儿科肿瘤，其预后较差。由于诸如高肿瘤异质性，多药耐药性，最小残留疾病等挑战，迫切需要探索新的NB治疗策略和有效治疗方法。本文中，在本研究中，我们探索了NB细胞对第二代组蛋白脱乙酰基酶抑制剂（HDACi）JNJ-26481585（JNJ）和溶血亲和剂氯喹（CQ）的未探索的反应，以及将其作为合理的治疗。我们发现，虽然JNJ单独诱导NB细胞自噬，但JNJ / CQ处理通过从自噬转变为凋亡降低了NB细胞的活力和增殖。进一步，我们发现通过CQ预处理抑制自噬导致ROS的产生和线粒体膜电位（MMP）的降低，随后导致NB细胞中caspase-3介导的凋亡细胞死亡。证实上述观察结果，我们发现ROS清道夫N-乙酰半胱氨酸（NAC）抵抗了caspase-3活性，并且使细胞免于凋亡。最后，这些观察结果表明，JNJ / CQ处理通过触发ROS的形成和MMP的破坏而导致NB细胞死亡，这表明CQ调节JNJ诱导的自噬代表了一种有希望的NB新治疗方法。我们发现ROS清除剂N-乙酰半胱氨酸（NAC）抵抗了caspase-3的活性，并从凋亡中拯救了细胞。最后，这些观察结果表明，JNJ / CQ处理通过触发ROS的形成和MMP的破坏而导致NB细胞死亡，这表明CQ调节JNJ诱导的自噬代表了一种有希望的NB新治疗方法。我们发现ROS清除剂N-乙酰半胱氨酸（NAC）抵抗了caspase-3的活性，并从凋亡中拯救了细胞。最后，这些观察结果表明，JNJ / CQ处理通过触发ROS的形成和MMP的破坏而导致NB细胞死亡，这表明CQ对JNJ诱导的自噬的调节代表了一种有希望的NB新治疗方法。