Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells
Yinghui Chen, Yongbo Zhao, Cuicui Wang, Xia Xiao, Xiaoyong Zhou, Guoxiong Xu
Med Sci Monit 2012; 18(10): BR383-388
Background: Several studies have shown that multidrug transporters, such as P-glycoprotein (PGP), are involved in cell resistance to chemotherapy and refractory epilepsy. The p38 mitogen-activated protein kinase (MAPK) signaling pathway may increase PGP activity. However, p38-mediated drug resistance associated with PGP is unclear. Here, we investigated p38-mediated doxorubicin-induced drug resistance in human leukemia K562 cells.
Material/Methods: The expression of PGP was detected by RT-PCR, Western blot, and immunocytochemistry. Cell viability and half-inhibitory concentrations (IC50) were determined by CCK-8 assay. The intracellular concentration of drugs was measured by HPLC.
Results: A doxorubicin-induced PGP overexpression cell line, K562/Dox, was generated. The p38 inhibitor SB202190 significantly decreased MDR1 mRNA expression, as well as PGP, in K562/Dox cells. The IC50 of phenytoin sodium and doxorubicin in K562/Dox cells was significantly higher than that in wild-type K562 cells, indicating the drug resistance of K562/Dox cells. During the blocking of p38 activity in the presence of SB202190, cell number was significantly reduced after the phenytoin sodium and doxorubicin treatment, and the IC50 of phenytoin sodium and doxorubicin was decreased in K562/Dox cells. HPLC showed that the intracellular levels of phenytoin sodium and doxorubicin were significantly lower in K562/Dox cells than those in K562 cells. The decrease of the intracellular level of these drugs was significantly abolished in the presence of SB202190.
Conclusions: Our study demonstrated that p38 is, at least in part, involved in doxorubicin-induced drug resistance. The mechanistic study of MAPK-mediated PGP and the action of SB202190 need further investigation.
Keywords: Phenytoin - pharmacology, P-Glycoprotein - metabolism, Leukemia - pathology, K562 Cells, Imidazoles, Drug Resistance, Neoplasm - drug effects, Doxorubicin - pharmacology, Dose-Response Relationship, Drug, Cell Survival - drug effects, Protein Kinase Inhibitors - pharmacology, Pyridines, p38 Mitogen-Activated Protein Kinases - metabolism