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 |
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Authors: | MASOUMEH OGHABI AVA SAFAROGHLI-AZAR ATIEH POURBAGHERI-SIGAROODI MOHAMMAD SAYYADI MOHSEN HAMIDPOUR MOHAMMAD HOSSEIN MOHAMMADI DAVOOD BASHASH |
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Affiliation: | 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 |
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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. |
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Keywords: | Chronic myeloid leukemia (CML) Cyclin-dependent kinase (CDK) AT7519 Autophagy PI3K c-Myc |
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