Valpronic Acid Ameliorates Acute Graft-versus-host Disease And Reverses Drug Resisita

Objective: As one of the most versatile families,Akt is not only involved in regulating the differentiation and immune function of T-cells,but also direct promting tumour cell survival.Therefore,the purpose of this study is to prove the unique role of VPA in controling acute graft-versus-host diseases and overcoming the drug resistance by inhibiting Akt signaling.Method: Administration of VPA in mouse model of MHC-mismatched Transplantation,we examined the expression and phosphorylation of Akt.Meanwhile,in the drug resistant AML cells,cell apoptosis can be measured by flow cytometry.The interaction between HDAC3 and Akt was revealed by Co-immunoprecipitation analysis.The expression and phosphorylation of Akt,HDAC3,cell cycle-related protein such as P21 and p27,DNA damage marker ?H2AX and DSB repair-related protein were detected by western blot analysis.Result: Upon VPA treatment in BMT recipients,western blot analysis showed that VPA downregulated the phosphorylation of Akt and downstream target protein.In addition,VPA also prevented Akt activation in the drug resistant AML cells.Further studies supported that combination with anticancer agents and VPA promoted cell apoptosis by impairing DNA repair response.Meanwhile,various studies revealed that VPA preferentially inhibited HDAC3,the finding that was associated with increased Akt acetylation and reduced phosphorylation of Akt.Conclusion: VPA ameliorates acute graft-versus-host disease and reverses drug resistance by regulating the interaction between Akt and HDAC3.