Artesunate enhances adriamycin cytotoxicity by inhibiting glycolysis in adriamycin-resistant chronic myeloid leukemia K562/ADR cells

Abstract

Adriamycin (ADR) is a widely used drug in multiple cancers including leukemia. Artesunate (ART) has been reported to improve the cytotoxicity of some chemotherapeutic drugs in cancers. However, it is still unknown whether ART can augment the cytotoxicity of ADR in ADR-resistant K562 leukemia cells (K562/ADR). Glycolytic activity was assessed by detecting glucose consumption, lactate production and glycolysis-related enzymes. MDR1 and ABCG2 mRNA levels were measured by RT-qPCR. Protein levels of P-glycoprotein (P-gp), ABCG2 and cytochrome c (Cyt c) were determined by western blot assay. Cell apoptosis was evaluated by flow cytometry. Cell viability was examined by CCK-8 assay. The results showed that K562/ADR cells exhibited increased glycolytic activity and mdr1 and abcg2 gene expression. ART potentiated ADR cytotoxicity in K562 and K562/ADR cells. Moreover, ART reversed ADR-induced mdr1 and abcg2 gene expression and inhibited P-gp and ABCG2 activities in K562/ADR cells. ART potentiated ADR-mediated inhibition on glycolysis in K562 and K562/ADR cells. Inhibition of glycolysis reduced cell viability, downregulated the expression of mdr1 and abcg2 genes, and induced cell apoptosis in K562/ADR cells. Overall, the results indicated that ART enhanced ADR cytotoxicity by inhibiting glycolysis and reducing mdr1 and abcg2 gene expression in K562/ADR cells, providing a deep insight into the function and molecular basis of ART in regulating MDR in leukemia cells and hinting at the potential values of ART in alleviating MDR in cancers.