Oncotarget

Research Papers:

Hsp90 N- and C-terminal double inhibition synergistically suppresses Bcr-Abl-positive human leukemia cells

Chun Chen, Yingting Zhuang, Xianling Chen, Xiaole Chen, Ding Li, Yingjuan Fan, Jianhua Xu _, Yuanzhong Chen and Lixian Wu

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Oncotarget. 2017; 8:10025-10036. https://doi.org/10.18632/oncotarget.14324

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Abstract

Chun Chen1,2,3, Yingting Zhuang1,2,3, Xianling Chen4, Xiaole Chen2,3,5, Ding Li1,2,3, Yingjuan Fan1,2,3, Jianhua Xu1,2,3, Yuanzhong Chen4, Lixian Wu1,2,3

1Deptartment of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China

2Institute of Materia Medica, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China

3Fuijan Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China

4Fujian Institute of Hematology, Union Hospital, FMU, Fuzhou, China

5Deptartment of Biopharmaceutics, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, China

Correspondence to:

Lixian Wu, email: wlx-lisa@126.com

Jianhua Xu, email: xjh@mail.fjmu.edu.cn

Yuanzhong Chen, email: chenyz@mail.fjmu.edu.cn

Keywords: Hsp90, amino terminal, carboxyl terminal, Bcr-Abl, imatinib-resistant

Received: July 07, 2016    Accepted: December 15, 2016    Published: December 28, 2016

ABSTRACT

Heat shock protein 90 (Hsp90) contains amino (N)–terminal domain, carboxyl(C)-terminal domain, and middle domains, which activate Hsp90 chaperone function cooperatively in tumor cells. One terminal occupancy might influence another terminal binding with inhibitor. The Bcr-Abl kinase is one of the Hsp90 clients implicated in the pathogenesis of chronic myeloid leukemia (CML). Present studies demonstrate that double inhibition of the N- and C-terminal termini can disrupt Hsp90 chaperone function synergistically, but not antagonistically, in Bcr-Abl-positive human leukemia cells. Furthermore, both the N-terminal inhibitor 17-AAG and the C-terminal inhibitor cisplatin (CP) have the capacity to suppress progenitor cells; however, only CP is able to inhibit leukemia stem cells (LSCs) significantly, which implies that the combinational treatment is able to suppress human leukemia in different mature states.


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