Hypomethylation agent decitabine restores drug sensitivity by depressing P-glycoprotein activity through MAPK signaling pathway.

Abstract

The multidrug resistance (MDR) continues to be an obstacle in the treatment of both hematological and solid tumors. Hypomethylation agent, decitabine (5-Aza-dC), is an experimental agent in MDR therapy, while the mechanism is not very clear. In the present study, we demonstrated 5-Aza-dC may reverse MDR induced by P-glycoprotein (P-gp) coded by mdr1 gene in both hematologic K562/ADR cells and solid tumor MCF-7/ADR cells with time and dose-dependent manner. 5-Aza-dC significantly increased drug sensitivity in patients' leukemic cells which had higher expression of mdr1 gene. Both total protein and membrane P-gp expression were up-regulated with 5-Aza-dC treatment in K562/ADR and MCF-7/ADR cells. However, accumulation of adriamycin and rhodamine 123 were increased which suggested the depression of P-gp activity. Gene expression profiling was performed and activation of MAPK signaling pathway was identified as the most significant change affected by 5-Aza-dC. Inhibition of MAPK pathway could increase P-gp activity. Our data suggested that hypomethylation agent decitabine restores drug sensitivity in the P-gp-induced MDR phenotype by depressing of P-gp activity as drug pump partly through MAPK signaling pathway.