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Oncotarget. 2016 Jun 7;7(23):34785-99. doi: 10.18632/oncotarget.9185.

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

Author information

1
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, School of Life Sciences, Jilin University, Changchun, China.
2
Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
3
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
4
Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
5
Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, China.
6
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
7
Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, China.

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.

KEYWORDS:

ABT-199; CHK1; LY2603618; Mcl-1; acute myeloid leukemia

PMID:
27166183
PMCID:
PMC5085189
DOI:
10.18632/oncotarget.9185
[Indexed for MEDLINE]
Free PMC Article

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