The Hypomethylating Agent 5-Azacitidine Potentiates the Effect of RAS and Sp1 Inhibitors in Neuroblastoma Cells.
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Neuroblastoma is a malignant solid tumor caused by the transformation of neural crest cells. Neuroblastoma predominantly occurs in children and is associated with a poor prognosis. In this regard, the development of novel approaches to neuroblastoma treatment, including combination therapy, is relevant. DNA hypermethylation of neuroblastoma cells indicates that it is possible to use hypomethylating agents in a combination therapy of the disease. In order to identify effective combinations of antitumor drugs, we analyzed the transcriptomic changes that take place in neuroblastoma SH-SY5Y cells after treatment with the hypomethylating agent 5-azacitidine and then experimentally tested the effectiveness of these combinations. Mithramycin A and lonafarnib were the two drugs that, in combination with 5-azacitidine, appeared to exert a synergistic effect on SH-SY5Y cell death. These drugs inhibit the signaling pathway associated with the transcription factor Sp1 and RAS-MAPK signaling pathway, which are activated by 5-azacitidine. An analysis of the signaling pathways also revealed an activation of the signaling pathways associated with neuroblastoma cell differentiation, as well as apoptosis induction, as confirmed by multiplex and confocal microscopy. Hence, by analyzing the changes in the signaling pathways, the mechanisms of cell death and cell adaptation to hypomethylating agents can be understood, and this can be further used to develop novel therapeutic approaches to neuroblastoma therapy.