Tetrandrine overcomes drug resistance mediated by bone marrow microenvironment by regulating the expression of P-glycoprotein in acute leukemia

Abstract

Objectives: To study the effect of TET on the reversal of drug resistance in the bone marrow microenvironment, and to further promote the research on drug reversal.Methods: We established a co-culture system of bone marrow mesenchymal stem cells (BM-MSC) and K562 cell lines, and compared the cell inhibition rate of K562 cells between the co-culture group and K562 singleculture group by daunorubicin (DNR) single-drug intervention with CCK-8 and also compared K562 proliferation in the co-culture group and K562 single-culture group after combined intervention with DNR and TET, then used Western blot and RT-qPCR to verify the expression of P-gp of K562 cells at protein and mRNA levels, confirmed the concentration of DNR in K562 of different experimental groups by HPLC-MS.Results: According to the results of CCK-8, after co-culture with bone marrow mesenchymal stem cells (BM-MSCs), the inhibition rate of DNR on K562 decreased significantly. When TET (1μmol/L) combined with daunorubicin (DNR) treated on the co-culture group, the inhibition rate increased significantly. Then, the results of RT-qPCR and western blot showed a remarkable difference of the expression of P-glycoprotein (P-gp). After co-culture with BM-MSCs, the protein expression of P-gp showed a significant upward trend. After adding TET intervention, the expression of P-gp decreased both in mRNA and protein levels. Also, the DNR concentration in K562 also performed the correspondent trend.Conclusion: The bone marrow microenvironment can promote the MDR of acute leukemia. TET can reverse the MDR mediated by the bone marrow microenvironment by inhibiting the expression of P-glycoprotein.

Keywords

• tetrandrine
• bone marrow microenvironment
• leukemia
• drug resistance reversal
• p-glycoprotein