Exploring the Drug Repurposing Versatility of Valproic Acid as a Multifunctional Regulator of Innate and Adaptive Immune Cells

Figure 7

VPA reduces the cytolytic activity in NK lymphocytes against tumor cells. VPA reduces the expression of certain receptors that participate in the identification of tumor cells, including NKp46, NKp30 (not shown), and NKG2D. This last system of receptors recognizes overexpressed stress molecules (UBLP3/MIC) in malignant cells, which leads to the activation of different lytic-related activation pathways in the NK cell. It is feasible that VPA affects these pathways, including IFN-γ secretion by reducing STAT5 phosphorylation, as well as the production of both granzyme B and perforin, which are intimately linked to cellular degranulation. VPA also diminishes NF-κB activation and the expression of NKG2D, by promoting the acetylation and methylation of the H3 histone that is next to the locus of this gene, and it blocks HDAC3, which strongly impacts STAT3 phosphorylation, which is required for the expression of this receptor. Furthermore, VPA blocks the cell cycle progression and increases the expression of both PD1 and the death ligand PD-L1, which is correlated with an increase in caspase expression and therefore with apoptosis. Green arrows indicate the processes, molecules, or mediators in the signaling pathway that are augmented and/or promoted by VPA. Red arrows indicate processes, molecules, or mediators in the signaling pathway that are inhibited by VPA.