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Neuroblastoma (NB) is the most common childhood cancer that arises from the sympathetic nervous system. NB is characterized by poor prognosis. One of the strategies to control NB is activating the differentiation process in undifferentiated NB cells. Many differentiating agents including 13-cis-retinoic acid (RA) led to disappointing results. In the current study, we investigated the effect of Quisinostat/JNJ-26481585(JNJ) on NB SK-N-SH cells differentiation. The SK-N-SH cell differentiation was observed by morphology and neurite length measurement. The cell cycle arrest was determined by FACS analysis. The relative levels of autophagy marker LC3-II, neuronal markers βIII-tubulin and Eno-2, cell cycle related proteins cyclin D1 and CDK 4 were detected by western blotting. JNJ induces differentiation in SK-N-SH cells, as evident by the morphological features and expression of neuronal markers, βIII-tubulin and Eno-2. Cell cycle arrest at G1 phase was confirmed by a decrease in the expression of cyclin D1 and CDK 4. Furthermore, we also observed that autophagy plays an important role in JNJ induced cell differentiation of SK-N-SH cells. We demonstrated that autophagy is induced upon JNJ treatment and is important for the neuronal differentiation of human SK-N-SH cells.

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.