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NVP-AUY922, a novel HSP90 inhibitor, inhibits the progression of malignant pheochromocytoma in vitro and in vivo

Authors Lian JP, Lin D, Xie X, Xu Y, Xu L, Meng L, Zhu Y

Received 14 December 2016

Accepted for publication 13 March 2017

Published 19 April 2017 Volume 2017:10 Pages 2219—2226

DOI https://doi.org/10.2147/OTT.S130236

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 2

Editor who approved publication: Dr Faris Farassati

Jianpo Lian,1,* Dengqiang Lin,1,* Xing Xie,1,* Yunze Xu,2 Lieyu Xu,1 Li Meng,1 Yu Zhu1

1Department of Urology, Ruijin Hospital, 2Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Purpose: Malignant pheochromocytoma (PCC) is a rare tumor with a very poor prognosis and no effective treatments. The aim of this study was to assess the efficacy of a novel second-generation synthetic heat-shock protein 90 (HSP90) inhibitor, NVP-AUY922, to treat malignant PCC in vitro and in vivo.
Materials and methods: Cell Counting Kit-8 (CCK-8) and Transwell assays were used to assess the effects of NVP-AUY922 on the proliferation and migration of the PCC cell line PC12. Flow cytometry was used to determine the effects of NVP-AUY922 on apoptosis and cell-cycle progression. Activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB/AKT) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling was measured using a Western blot analysis. In vivo, a mouse xenograft model was used to test the effects of intraperitoneal injection of NVP-AUY922 on tumor growth.
Results: NVP-AUY922 was found to be cytotoxic in PC12 cells at lower concentrations compared with 17-allylamino-17-demethoxygeldanamcyin (17-AAG). NVP-AUY922 inhibited the proliferation of PC12 cells in a time- and concentration-dependent manner and decreased the rate of migration of PC12 cells. Furthermore, we found that HSP90 inhibition induced cell-cycle arrest and apoptosis. In vivo, administration of NVP-AUY922 reduced PCC tumor growth without significant weight loss. Finally, we observed the modulation of MEK/ERK and PI3K/AKT signaling in response to NVP-AUY922 exposure.
Conclusion: NVP-AUY922 exhibits potent anti-PCC activities in vitro and in vivo and represents a promising therapeutic small molecule for treating malignant PCC.

Keywords: pheochromocytoma, HSP90, NVP-AUY922, xenograft model, therapy
 

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