Arsenic trioxide reduces drug resistance to adriamycin in leukemic K562/A02 cells via multiple mechanisms

Abstract: The present study aimed to study the mechanisms by which low dose arsenic trioxide (As2O3) reduces multidrug resistance. The potential influence of As2O3 on cytotoxicity was examined by methyl thiazolyl tetrazolium (MTT) assay and the intracellular mean fluorescence intensity (MFI) of Adriamycin (ADM) was examined by flow cytometry. The gene expression of mdr1 mRNA was determined by RT-PCR. The change of cellular expression levels of drug resistant-related proteins, including P-gp, bcl-2, Topo-II, and GST-π, were measured by Western-blotting or immunocytochemistry assay. Data showed As2O3 at non-cytotoxic concentration (2μM) significantly increased the cytotoxicity of ADM on K562/A02 cells. Cotreatment of As2O3 and ADM significantly increased the ADM MFI than ADM alone (P <0.01). Following pretreatment of K562/A02 cells with As2O3, the expression of Topo-II was increased while the expression of GST-π and bcl-2 was decreased. No obvious alternation of expression of mdr1 mRNA or P-gp was observed. Thus, low dose As2O3 partially reduced drug resistance to ADM in K562/A02 cells via multiple mechanisms, which selectively inhibited the efflux pump GST-π but not P-gp, as well as modulated the expression of MDR-related proteins such as Topo-II and bcl-2, in line with previous studies. In conclusions: The effect of As2O3 on reducing MDR may have wide clinical application in chemotherapy regimens for leukemia. [Copyright &y& Elsevier]