CDK Blockade Using AT7519 Suppresses Acute Myeloid Leukemia Cell Survival through the Inhibition of Autophagy and Intensifies the Anti-leukemic Effect of Arsenic Trioxide

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.

Abstract

The strong storyline behind the critical role of cyclin-dependent kinase (CDK) inhibitor proteins
in natural defense against malignant transformation not only represents a heroic perspective for
these proteins, but also provides a bright future for the application of small molecule inhibitors
of CDKs in the novel cancer treatment strategies. The results of the present study revealed that
the inhibition of CDKs using pan-CDK inhibitor AT7519, as revealed by the induction of G1
cell cycle arrest as well as the reduction of cyclins expression, resulted in decreased survival in
acute myeloid leukemia (AML)-derived KG-1 cells, either in the context of single agent or in
combination with arsenic trioxide (ATO). Apart from alterations in the expression of proliferation
and apoptotic genes, the anti-survival property of AT7519 was coupled with the inhibition of
autophagy-related genes. Notably, we found that the blockage of autophagy system in KG-1
cells resulted in a superior cytotoxic effect, introducing autophagy as a probable suppressor of
cell death. As far as we are aware, to date, no study has reported the contributory mechanisms
correlated with the less sensitivity of acute leukemia cells to AT7519 and our study suggested for
the first time that the activation of both PI3K and c-Myc signaling pathways could overshadow,
at least partly, the efficacy of this agent in KG-1 cells. Overall, due to the pharmacologic safety of
AT7519, our study proposed this inhibitor as a promising agent for the treatment of AML either
as a single agent or in a combined-modal strategy.

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Iranian Journal of Pharmaceutical Research

Volume 18, Special Issue
Autumn 2019
Pages 119-131

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