Hydroxychloroquine reverses the drug resistance of leukemic K562/ADMcells by inhibiting autophagy.

Abstract

Autophagy is an essential metabolic pathway mediated by lysosomal degradation, which is involved in scavenging and recycling senescent or damaged organelles and biological macromolecules in eukaryotic cells. The present study explored the association between the autophagic activity and chemotherapy resistance of leukaemia cells, and the possibility of using autophagy inhibitors to combat leukemic drug resistance. It was found that the levels of basic autophagy in multidrug‑resistant leukaemia cells(K562/ADM) were significantly higher compared with sensitive cells(K562), and that Adriamycin(ADM) was capable of inducing autophagic activity in K562 and K562/ADMcells. K562 and K562/ADMcells were treated with a series of hydroxychloroquine (HCQ) concentrations to inhibit cellular autophagy and detect cell sensitivity to ADM. The results demonstrated that the sensitivity of K562cells to ADM was mildly enhanced by HCQ, and that the sensitivity of K562/ADMcells to ADM was markedly strengthened by HCQ. In addition, more typical morphological changes associated with apoptosis emerged, and the ratio of Bax/Bcl‑2 and activity of caspase‑3 were markedly increased in K562/ADMcells treated with HCQ. Notably, the expression of mdr1 mRNA and P‑glycoprotein(P‑gp) in drug‑resistant K562/ADMcells was upregulated along with increasing autophagic activity induced by ADM. Furthermore, HCQ significantly reduced the increase in P‑gp expression by inhibiting autophagic activity. Collectively, these findings indicated that the inhibition of autophagy significantly promoted the sensitivity of K562/ADMcells to ADM by facilitating apoptosis. Furthermore, inhibition of autophagy attenuated the expression of P‑gp; therefore, P‑gp may be involved in autophagic regulation in drug‑resistant cells.