Oncotarget

Research Papers:

Inhibition of CHK1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells

Jianyun Zhao, Xiaojia Niu, Xinyu Li, Holly Edwards, Guan Wang, Yue Wang, Jeffrey W Taub, Hai Lin and Yubin Ge _

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Oncotarget. 2016; 7:34785-34799. https://doi.org/10.18632/oncotarget.9185

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Abstract

Jianyun Zhao1,6, Xiaojia Niu1, Xinyu Li1, Holly Edwards2,3, Guan Wang1, Yue Wang4, Jeffrey W Taub5,6, Hai Lin7, Yubin Ge2,3

1National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, School of Life Sciences, Jilin University, Changchun, China

2Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA

3Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

4Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, China

5Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA

6Division of Pediatric Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI, USA

7Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, China

Correspondence to:

Yubin Ge, email: gey@karmanos.org

Hai Lin, email: maillinhai@sina.com

Jeffrey W Taub, email: jtaub@med.wayne.edu

Keywords: LY2603618, ABT-199, acute myeloid leukemia, CHK1, Mcl-1

Received: February 29, 2016     Accepted: April 16, 2016     Published: May 05, 2016

ABSTRACT

Resistance to standard chemotherapy agents remains a major obstacle for improving treatment outcomes for acute myeloid leukemia (AML). The Bcl-2-selective inhibitor ABT-199 has demonstrated encouraging preclinical results, drug resistance remains a concern. Mcl-1 has been demonstrated to contribute to ABT-199 resistance, thus combining with therapies that target Mcl-1 could overcome such resistance. In this study, we utilized a CHK1 inhibitor, LY2603618, to decrease Mcl-1 and enhance ABT-199 efficacy. We found that LY2603618 treatment resulted in abolishment of the G2/M cell cycle checkpoint and increased DNA damage, which was partially dependent on CDK activity. LY2603618 treatment resulted in decrease of Mcl-1, which coincided with the initiation of apoptosis. Overexpression of Mcl-1 in AML cells significantly attenuated apoptosis induced by LY2603618, confirming the critical role of Mcl-1 in apoptosis induced by the agent. Simultaneous treatment with LY2603618 and ABT-199 resulted in synergistic induction of apoptosis in both AML cell lines and primary patient samples. Our findings provide new insights into overcoming a mechanism of intrinsic ABT-199 resistance in AML cells and support the clinical development of combined ABT-199 and CHK1 inhibition.


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