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The synergistic antileukemic effects of eltrombopag and decitabine in myeloid leukemia cells

Authors Shi M, Xu F, Yang X, Bai Y, Niu J, Drokow EK, Chen M, Chen Y, Sun K

Received 8 May 2019

Accepted for publication 5 August 2019

Published 6 September 2019 Volume 2019:11 Pages 8229—8238

DOI https://doi.org/10.2147/CMAR.S213931

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo


Mingyue Shi,1–3 Fangfang Xu,4 Xiawan Yang,2 Yanliang Bai,2 Junwei Niu,2 Emmanuel Kwateng Drokow,2 Mingyi Chen,3 Yuqing Chen,2 Kai Sun2

1Division of Graduate, Department of Hematology, The Second Clinical Medical School and the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China; 3Department of Pathology and Laboratory Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; 4Department of Research and Discipline Development, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China

Correspondence: Kai Sun; Yuqing Chen
Department of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, #7 Weiwu Road, Zhengzhou 450003, Henan, People’s Republic of China
Tel +86 182 3711 0038
Email sunkai@cellscience.org
henanblood@sina.com

Background: Hypomethylating agents (HMAs), such as decitabine (DAC), are currently used as first-line therapy for patients with high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) not eligible for standard chemotherapies. Exacerbation of thrombocytopenia is one of the prevalent complications after HMA treatment. Eltrombopag (EP), an oral thrombopoietin receptor agonist, can efficiently stimulate megakaryopoiesis and elevate platelet counts in MDS/AML patients. However, the significance of combining EP with HMAs in patients with high-risk MDS/AML has not been determined.
Purpose: To explore the impacts and mechanisms of EP and/or DAC on leukemia cell growth and to explore whether EP exhibits antileukemic effects in the context of DAC treatment in human myeloid leukemia cell lines.
Methods: In our study, we assessed the anti-leukemic effect of EP in the context of DAC treatment by measuring cell proliferation, apoptosis, cell-cycle distribution, and intracellular reactive oxygen species (ROS) levels.
Results: Our results showed that the combination of EP and DAC had a more obvious antiproliferative effect than that of DAC as a single agent. EP mainly induced S or G0/G1 phase cell cycle arrest, and DAC arrested the cell cycle in the S or G2/M phase. The combination of EP and DAC had a synergistic effect on cell cycle arrest. Furthermore, single-agent treatment with EP or DAC induced a change in intracellular ROS levels, and the combination of EP and DAC had a synergistic effect on ROS levels, exacerbating leukemia cell death.
Conclusion: Our study provides in vitro evidence of the synergistic antileukemic effect and potential mechanisms of the combination of DAC and EP on myeloid leukemia cells.

Keywords: eltrombopag, decitabine, myeloid leukemia, reactive oxygen species, ROS
 

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