The anticancer effects of pharmacological inhibition of autophagy in acute erythroid leukemia cells. Issue 10 (November 2018)

• Record Type: Journal Article
• Authors: Kazemi, Alireza; Sadri, Mohammadreza; Houshmand, Mohammad; Yazdi, Narjes; Zarif, Mahin Nikougoftar; Anjam-Najmedini, Ali; Tavakoli, Rezvan; Ojaghi, Mohammad; Ajami, Mansoureh; Ajami, Monireh; Atashi, Amir
• Is Part Of: Anti-cancer drugs. Volume 29:Issue 10(2018)
• Publication Date: 2018-11
• Subjects: 3-methyladenine -- autophagy -- chloroquine -- c-Myc -- leukemia -- micro-RNAs; Antineoplastic agents -- Periodicals; Cancer -- Chemotherapy -- Periodicals; Antineoplastic Agents -- therapeutic use -- Periodicals; Drug Therapy -- Periodicals; 616.994061
• DOI: 10.1097/CAD.0000000000000668
• Languages: English
• ISSNs: 0959-4973

Abstract

Abstract : 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.