Comparative effects of SNX-7081 and SNX-2112 on cell cycle, apoptosis and Hsp90 client proteins in human cancer cells

Wang,Xiao; Wang,Shaoxiang; Liu,Yuting; Huang,Dane; Zheng,Kai; Zhang,Yi; Wang,Xiaoyan; Liu,Qiuying; Yang,Depo; Wang,Yifei

doi:10.3892/or.2014.3552

Comparative effects of SNX-7081 and SNX-2112 on cell cycle, apoptosis and Hsp90 client proteins in human cancer cells

Authors:
- Xiao Wang
- Shaoxiang Wang
- Yuting Liu
- Dane Huang
- Kai Zheng
- Yi Zhang
- Xiaoyan Wang
- Qiuying Liu
- Depo Yang
- Yifei Wang
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Affiliations: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China, Guangdong Province Engineering Technology Research Institute of Traditional Chinese Medicine, Guangzhou, Guangdong 510095, P.R. China, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
Published online on: October 20, 2014 https://doi.org/10.3892/or.2014.3552
Pages: 230-238

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Abstract

SNX-2112, a novel 2-aminobenzamide inhibitor of Hsp90, previously showed a broad spectrum of anticancer activity. However, subsequent development has been discontinued due to ocular toxicity as identified in a phase I study. SNX-7081, another closely related Hsp90 inhibitor with a side chain of indole instead of indazole, has recently attracted attention. The aim of the present study was to investigate the anticancer effects of SNX-7081 in eleven cell lines, as well as the mechanisms involved, with SNX-2112 serving as a reference. The cytotoxic effects were determined using an MTT assay and apoptosis was measured using flow cytometry. The results showed that SNX-7081 exerted better inhibitory effects than SNX-2112 in six eighths of the human cancer cell lines, with an average IC50 of 1 µM. The two inhibitors exerted low cytotoxicity in L-02, HDF and MRC5 normal human cells (IC50 >50 µM), and arrested cancer cells at the G2/M phase in a similar manner to normal cells. Compared with SNX-2112, SNX-7081 exhibited more potent effects on cell apoptosis in four sixths of the human cancer cell lines, and was more active in the downregulation of Hsp90 client proteins. In addition, SNX-7081 exhibited a stronger binding affinity to Hsp90 than SNX-2112 in molecular docking experiments. Considering the superior effects against Hsp90 affinity, cell growth, apoptosis, and Hsp90 client proteins in a majority of human cancer cells, the novel SNX-7081 may be a promising alternative to SNX-2112, which merits further evaluation.

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