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The anticancer effects of pharmacological inhibition of autophagy in acute erythroid leukemia cells

Kazemi, Alirezaa; Sadri, Mohammadrezaa; Houshmand, Mohammadh; Yazdi, Narjesb; Zarif, Mahin Nikougoftarc; Anjam-Najmedini, Alia; Tavakoli, Rezvand; Ojaghi, Mohammadf; Ajami, Mansourehe; Ajami, Monirehe; Atashi, Amirg

doi: 10.1097/CAD.0000000000000668
PRECLINICAL REPORTS

Although recent studies have reported different aspects of autophagy, from pro-survival to pro-death roles of this process in malignant cells, the underlying mechanisms by which autophagy inhibitors contribute toward the induction of programmed cell death in cancerous cells are still unclear. In the present study, we have attempted to explore some of the molecular features of pharmacological inhibition of autophagy in TF-1 cells (an acute erythroid leukemia model). Our findings indicated that ara-C induces autophagy (with alteration of LC3B, p62, and Beclin-1) in the cells; however, targeting autophagy by 3-methyladenine and chloroquine significantly increased caspase-dependent apoptosis and the sub-G1 compartment in ara-C-treated cells. Moreover, cell cycle analysis showed that 3-MA, as an early-stage autophagy inhibitor, could elevate the cell population in the G0/G1 cell cycle phase, which was associated with upregulation of p21 and p27 expressions. Interestingly, autophagy inhibition was also accompanied by downregulation of c-Myc gene and protein expression levels and upregulated levels of Bax and Bak gene expressions. In addition, following inhibition of autophagy, the levels of tumor-suppressive miRNA (i.e. miR-204) increased, whereas the values of oncogenic miRNAs (including miR-21, miR-221, miR-30a, and miR-17) decreased. Overall, our experiments indicate that autophagy inhibitors (especially chloroquine) seem to be promising agents for combination therapy in acute erythroid leukemia.

aDepartment of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences

bDepartment of Molecular Genetics, Tehran Medical Branch, Islamic Azad University

cBlood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine

dStem Cell Technology Research Center

eDepartment of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran

fDepartment of Molecular Biology, Faculty of Basic Science, Mazandaran University, Babolsar

gDepartment of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran

hDepartment of Clinical and Biological Sciences, University of Turin, Turin, Italy

Correspondence to Amir Atashi, PhD, Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud 3614773955, Iran Tel/fax: +98 233 239 4800; e-mail: atashia@shmu.ac.ir

Received April 1, 2018

Accepted June 21, 2018

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.