e-Article
Hydroxychloroquine reverses the drug resistance of leukemic K562/ADM cells by inhibiting autophagy
Document Type
Academic Journal
Author
Source
Molecular Medicine Reports. October 2019, Vol. 20 Issue 4, p3883, 10 p.
Subject
Language
English
ISSN
1791-2997
Abstract
Introduction Leukaemia, a clonal proliferative neoplasm derived from haematopoietic stem cells, is commonly caused by various genetic mutations (1). There are a variety of clinical therapies involving chemotherapy used to [...]
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/ADM cells. K562 and K562/ADM cells 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 K562 cells to ADM was mildly enhanced by HCQ, and that the sensitivity of K562/ADM cells 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/ADM cells treated with HCQ. Notably, the expression of mdrl mRNA and P-glycoprotein (P-gp) in drug-resistant K562/ADM cells 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/ADM cells 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. Key words: autophagy, drug resistance, apoptosis, P-glycoprotein, Leukaemia in cancer cells often leads to multidrug resistance by pumping agents out of cells (9).
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/ADM cells. K562 and K562/ADM cells 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 K562 cells to ADM was mildly enhanced by HCQ, and that the sensitivity of K562/ADM cells 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/ADM cells treated with HCQ. Notably, the expression of mdrl mRNA and P-glycoprotein (P-gp) in drug-resistant K562/ADM cells 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/ADM cells 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. Key words: autophagy, drug resistance, apoptosis, P-glycoprotein, Leukaemia in cancer cells often leads to multidrug resistance by pumping agents out of cells (9).