Vol.44, No.2, 2020, pp.183-192, doi:10.32604/biocell.2020.08880
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ARTICLE
Anti-proliferative effects of a small molecule inhibitor of CDK AT7519 on chronic myeloid leukemia (CML) cells through halting the transition of cells from G2/M phase of the cell cycle
  • MASOUMEH OGHABI1,2, AVA SAFAROGHLI-AZAR1,2, ATIEH POURBAGHERI-SIGAROODI1,2, MOHAMMAD SAYYADI3, MOHSEN HAMIDPOUR1, MOHAMMAD HOSSEIN MOHAMMADI1, DAVOOD BASHASH1,*
1 Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3 School of Allied Medical Sciences, Arak University of Medical Sciences, Arak, Iran
* Address correspondence to: Davood Bashash, d.bashash@sbmu.ac.ir
Received 21 October 2019; Accepted 16 December 2019; Issue published 27 May 2020
Abstract
Pathogenesis of chronic myeloid leukemia (CML) has mostly been studied with regard to the oncogenic role of BCR/ABL fusion; however, recent disclosures have declared that the challenges with the treatment of CML patients would not be resolved until the role of other aberrancies is ignored. Given the involvement of cyclin-dependent kinases (CDKs) in the pathogenesis of CML, the present study aimed to investigate the effects of a multi-CDK inhibitor AT7519 on BCR/ABL-harboring CML-derived K562 cells. Our results showed that AT7519 effectively reduced the survival of K562 and induced its anti-proliferative effect through the induction of G2/M arrest due to elevated p21 and p27. The resulting data also revealed that either direct or indirect suppression of c-Myc using specific c-Myc inhibitor 10058-F4 and selective PI3K inhibitor CAL-101 resulted in a superior cytotoxicity, suggesting that the activation of PI3K pathway could attenuate antileukemic effects of the inhibitor, at least partly, through a c-Mycdependent mechanism. To the best of our knowledge, to date, no study has addressed the effect of autophagy on CML cell response to AT7519, and, herein, we proposed for the first time that the suppression of autophagy boosted AT7519 cytotoxicity against K562. Overall, we suggested that selective CDK inhibitor AT7519 exerted antileukemic effect against CML cells and propose a novel therapeutic application for the inhibitor either as a single agent or in combination with c-Myc and/or PI3K inhibitors.
Keywords
Chronic myeloid leukemia (CML), Cyclin-dependent kinase (CDK), AT7519, Autophagy, PI3K, c-Myc
Cite This Article
OGHABI, M., SAFAROGHLI-AZAR, A., POURBAGHERI-SIGAROODI, A., SAYYADI, M., HAMIDPOUR, M. et al. (2020). Anti-proliferative effects of a small molecule inhibitor of CDK AT7519 on chronic myeloid leukemia (CML) cells through halting the transition of cells from G2/M phase of the cell cycle. BIOCELL, 44(2), 183–192.
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