Napabucasin (BBI608) eliminate AML cells in vitro and in vivo via inhibition of Stat3 pathway and induction of DNA damage

doi:10.1016/j.ejphar.2019.05.020

. 2019 Jul 15:855:252-261.

doi: 10.1016/j.ejphar.2019.05.020. Epub 2019 May 11.

Napabucasin (BBI608) eliminate AML cells in vitro and in vivo via inhibition of Stat3 pathway and induction of DNA damage

Silei Bi¹, Kai Chen², Liying Feng³, Guofeng Fu⁴, Qianying Yang⁴, Manman Deng³, Haijun Zhao³, Zhifeng Li³, Lian Yu⁵, Zhihong Fang⁶, Bing Xu⁷

Affiliations

¹ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Department of Hematology, Heze Municipal Hospital, Heze, 274031, PR China.
² The First People's Hospital of Foshan (The Affiliated Foshan Hospital of Sun Yat-sen University), Foshan, 528000, PR China; Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, PR China.
³ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China.
⁴ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361102, PR China.
⁵ Department of Hematology and Rheumatology, Longyan First Hospital, Affiliated to Fujian Medical University, Longyan, 364000, PR China. Electronic address: yulian_ly@126.com.
⁶ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China. Electronic address: jeho_fang@126.com.
⁷ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China. Electronic address: xubingzhangjian@126.com.

PMID: 31085238
DOI: 10.1016/j.ejphar.2019.05.020

Napabucasin (BBI608) eliminate AML cells in vitro and in vivo via inhibition of Stat3 pathway and induction of DNA damage

Silei Bi et al. Eur J Pharmacol. 2019.

. 2019 Jul 15:855:252-261.

doi: 10.1016/j.ejphar.2019.05.020. Epub 2019 May 11.

Authors

Silei Bi¹, Kai Chen², Liying Feng³, Guofeng Fu⁴, Qianying Yang⁴, Manman Deng³, Haijun Zhao³, Zhifeng Li³, Lian Yu⁵, Zhihong Fang⁶, Bing Xu⁷

Affiliations

¹ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Department of Hematology, Heze Municipal Hospital, Heze, 274031, PR China.
² The First People's Hospital of Foshan (The Affiliated Foshan Hospital of Sun Yat-sen University), Foshan, 528000, PR China; Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, PR China.
³ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China.
⁴ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361102, PR China.
⁵ Department of Hematology and Rheumatology, Longyan First Hospital, Affiliated to Fujian Medical University, Longyan, 364000, PR China. Electronic address: yulian_ly@126.com.
⁶ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China. Electronic address: jeho_fang@126.com.
⁷ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China. Electronic address: xubingzhangjian@126.com.

PMID: 31085238
DOI: 10.1016/j.ejphar.2019.05.020

Abstract

Acute myeloid leukemia (AML) is a heterogeneous malignancy of hematopoietic stem cells with poor clinical outcome despite recent improvements in chemotherapy and stem cell transplantation regimens. Thus, new therapeutic agents are urgently needed in order to prolong the disease-free survival of AML patients in clinic. Here, we report that BBI608 is highly active against diverse AML cell lines in vitro and primary samples obtained from patients with AML ex vivo, as well as effective in vivo in AML xenograft models. Meanwhile, the anti-AML property of BBI608 is closely associated with the inhibition of Stat3 pathway and induction of DNA damage. Of note, BBI608 combined with Bcl-2 inhibitor (i.e., ABT-199) exerts a significantly enhanced anti-leukemia effect in BBI608-resistant cell line Kasumi-1. Together, the present findings suggest that BBI608 might represent a potential candidate agent for AML treatment.

Keywords: AML; BBI608; DNA damage; Stat3.

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Napabucasin (BBI608) eliminate AML cells in vitro and in vivo via inhibition of Stat3 pathway and induction of DNA damage

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Napabucasin (BBI608) eliminate AML cells in vitro and in vivo via inhibition of Stat3 pathway and induction of DNA damage

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