Selective inhibition of Aurora A and B kinases effectively induces cell cycle arrest in t(8;21) acute myeloid leukemia.

Abstract

The fusion gene AML1-ETO initially dysregulates various cell cycle molecules in t(8;21) acute myeloid leukemia. Aurora kinases have shown great promise in treating tumors. However, the efficacy of Aurora kinase (AURK) A and B inhibition in t(8;21) AML remains unclear. We found that AURK-A inhibitor Alisertib and AURK-B inhibitor Barasertib strongly inhibited the growth and proliferation of t(8;21) AML cells. The quantity and size of cell colonies were markedly decreased after a 14-d drug exposure. The cell cycle distribution was blocked at the G2/M phase in both dose- and time-dependent manner. The expression of p53 family and cdc2-p34 significantly changed as well. Notably, we found that t(8;21) AML cells are more sensitive to Aurora B inhibition. In each set of experiments, Barasertib took less time or a lower concentration to achieve similar efficacy. Taken together, our data highlighted the potential role of Aurora kinases as promising cell cycle targets for the treatment of t(8;21) AML and hereby provided a theoretical basis to guide relevant clinical trials.

• Authors: Jialei Qi, Xiang Gao, Xiaomin Zhong, Ninghan Zhang, Rong Wang, Huihui Zhang, Ting Pan, Xuejiao Liu, Yao Yao, Qingyun Wu, Mingshan Niu, Kailin Xu
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 117 Pg. 109113 (Sep 2019) ISSN: 1950-6007 [Electronic] France
• PMID: 31207577 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• 2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
• Azepines
• Cell Cycle Proteins
• MLN 8237
• Organophosphates
• Protein Kinase Inhibitors
• Pyrimidines
• Quinazolines
• Aurora Kinase A
• Aurora Kinase B

Topics

• Aurora Kinase A (antagonists & inhibitors, metabolism)
• Aurora Kinase B (antagonists & inhibitors, metabolism)
• Azepines (pharmacology)
• Cell Cycle Checkpoints (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromosomes, Human, Pair 21 (genetics)
• Chromosomes, Human, Pair 8 (genetics)
• Humans
• Leukemia, Myeloid, Acute (genetics, pathology)
• Organophosphates (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Quinazolines (pharmacology)
• Time Factors
• Translocation, Genetic
• Tumor Stem Cell Assay