Hydroxychloroquine reverses the drug resistance of leukemic K562/ADM cells by inhibiting autophagy

Wang,Feifei; Zhang,Zhewen; Leung,Wing  Ting; Chen,Jing; Yi,Juan; Ying,Chunmei; Yuan,Minmin; Wang,Mingyan; Zhang,Na; Qiu,Xuemin; Wang,Ling; Wei,Hulai

doi:10.3892/mmr.2019.10621

Hydroxychloroquine reverses the drug resistance of leukemic K562/ADM cells by inhibiting autophagy

Authors:
- Feifei Wang
- Zhewen Zhang
- Wing Ting Leung
- Jing Chen
- Juan Yi
- Chunmei Ying
- Minmin Yuan
- Mingyan Wang
- Na Zhang
- Xuemin Qiu
- Ling Wang
- Hulai Wei
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Affiliations: Department of Laboratory Medicine, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China, Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, P.R. China
Published online on: August 27, 2019 https://doi.org/10.3892/mmr.2019.10621
Pages: 3883-3892
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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/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 mdr1 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.

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