Inhibition of Cyclin-dependent Kinase (CDK) Decreased Survival of NB4 Leukemic Cells: Proposing a p53-Independent Sensitivity of Leukemic Cells to Multi-CDKs Inhibitor AT7519

Document Type: Research article

Authors

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 Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract

An unbounded number of events exist beneath the intricacy of each particular hematologic malignancy, prompting the tumor cells into an unrestrained proliferation and invasion. Aberrant expression of cyclin-dependent kinases (CDKs) is one of these events which disrupts regulation of cell cycle and subsequently, results in cancer progression. In this study, we surveyed the repressive impact of multi-CDK inhibitor AT7519 on a panel of leukemia-derived cell lines. Our data underlined that AT7519 abated the survival of all tested cells; however, in an overview, the response rate of leukemic cells to the inhibitor was varied irrespective of p53 status. Notably, the less sensitivity of leukemia cells to AT7519 was found to be mediated partly by the compensatory activation of c-Myc oncogene which was confirmed by the induction of a superior cytotoxicity upon its suppression in less sensitive cell. The blockage of cell cycle, as announced by induction of sub-G1 arrest as well as reduced S phase, resulted in a significant decrease in survival of acute promyelocytic leukemia (APL)-derived NB4 cells, as the most sensitive cell line, either as monotherapy or in combination with arsenic trioxide. Anti-leukemic effects of the inhibitor were further verified by apoptosis analysis, where we discovered that AT7519 induced apoptosis via alteration of pro- and anti-apoptotic genes in NB4. All in all, this study proposed that AT7519 is a rewarding agent opposed to APL; however, additional examinations should be performed to determine the advantages of this inhibitor in clinical setting.

Graphical Abstract

Inhibition of Cyclin-dependent Kinase (CDK) Decreased Survival of NB4 Leukemic Cells: Proposing a p53-Independent Sensitivity of Leukemic Cells to Multi-CDKs Inhibitor AT7519

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