Inhibition of CHK1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells
Metrics: PDF 1797 views | HTML 2039 views | ?
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
Yubin Ge, email: email@example.com
Hai Lin, email: firstname.lastname@example.org
Jeffrey W Taub, email: email@example.com
Keywords: LY2603618, ABT-199, acute myeloid leukemia, CHK1, Mcl-1
Received: February 29, 2016 Accepted: April 16, 2016 Published: May 05, 2016
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.