Oncotarget

Research Papers:

Inhibition of Bcl-xL overcomes polyploidy resistance and leads to apoptotic cell death in acute myeloid leukemia cells

Weihua Zhou, Jie Xu, Elise Gelston, Xing Wu, Zhengzhi Zou, Bin Wang, Yunxin Zeng, Hua Wang, Anwen Liu, Lingzhi Xu and Quentin Liu _

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Oncotarget. 2015; 6:21557-21571. https://doi.org/10.18632/oncotarget.4306

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Abstract

Weihua Zhou1,2,*, Jie Xu1,2,*, Elise Gelston3,*, Xing Wu1, Zhengzhi Zou4, Bin Wang5, Yunxin Zeng6, Hua Wang7, Anwen Liu2, Lingzhi Xu8 and Quentin Liu1,8

1 State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China

2 Department of Oncology, the Second Affiliated Hospital, Nanchang University, Nanchang, China

3 University of Michigan Medical School, Ann Arbor, Michigan, United States

4 MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China

5 Department of Ultrasound, Union Hospital, Tongji Medical Collage of Huazhong University of Science and Technology, Wuhan, China

6 Department of Hematology, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China

7 Department of Hematological Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, China

8 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China

* These authors have contributed equally to this work

Correspondence to:

Quentin Liu, email:

Weihua Zhou, email:

Keywords: mitotic slippage, polyploidy, resistance, Bcl-xL, targeted therapy

Received: January 20, 2015 Accepted: May 13, 2015 Published: May 27, 2015

Abstract

Small molecular inhibitors or drugs targeting specific molecular alterations are widely used in clinic cancer therapy. Despite the success of targeted therapy, the development of drug resistance remains a challenging problem. Identifying drug resistance mechanisms for targeted therapy is an area of intense investigation, and recent evidence indicates that cellular polyploidy may be involved. Here, we demonstrate that the cell cycle kinase inhibitor, Oxindole-1 (Ox-1), induces mitotic slippage, causing resistant polyploidy in acute myeloid leukemia (AML) cells. Indeed, Ox-1 decreases the kinase activity of CDK1 (CDC2)/cyclin B1, leading to inhibition of Bcl-xL phosphorylation and subsequent resistance to apoptosis. Addition of ABT-263, a Bcl-2 family inhibitor, to Ox-1, or the other polyploidy-inducer, ZM447439 (ZM), produces a synergistic loss of cell viability with greater sustained tumor growth inhibition in AML cell lines and primary AML blasts. Furthermore, genetic knockdown of Bcl-xL, but not Bcl-2, exhibited synergistic inhibition of cell growth in combination with Ox-1 or ZM. These data demonstrate that Bcl-xL is a key factor in polyploidization resistance in AML, and that suppression of Bcl-xL by ABT-263, or siRNAs, may hold therapeutic utility in drug-resistant polyploid AML cells.


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