Collectively, this study suggests that S(+)-ibuprofen can reduce the malignancy of unfavorable neuroblastoma cells by modulating the expression of MYC, MYCN, AKT and p53, by changing the gene expression profile towards a less aggressive phenotype and by inducing UPR, which may link to destabilization of MYC and MYCN. Here, AKT1 is linked to neuroblastoma.