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Inhibition of heat-shock protein 90 sensitizes liver cancer stem-like cells to magnetic hyperthermia and enhances anti-tumor effect on hepatocellular carcinoma-burdened nude mice

Authors Yang R, Tang QS, Miao FQ, An YL, Li MF, Han Y, Wang XH, Wang J, Liu PD, Chen R

Received 4 August 2015

Accepted for publication 31 October 2015

Published 7 December 2015 Volume 2015:10(1) Pages 7345—7358

DOI https://doi.org/10.2147/IJN.S93758

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Lakshmi Kiran Chelluri

Peer reviewer comments 3

Editor who approved publication: Dr Lei Yang

Rui Yang,1,* Qiusha Tang,1,* Fengqin Miao,1 Yanli An,2 Mengfei Li,1 Yong Han,1 Xihui Wang,1 Juan Wang,3 Peidang Liu,1 Rong Chen4

1School of Medicine, Southeast University, 2Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Nanjing, 3Department of Infectious Disease, The Third People’s Hospital of Nantong, Nangtong; 4Department of Oncology, Zhongda Hospital, Nangjing, Jiangsu Province, People’s Republic of China

*These authors contributed equally to this work

Purpose: To explore the thermoresistance and expression of heat-shock protein 90 (HSP90) in magnetic hyperthermia-treated human liver cancer stem-like cells (LCSCs) and the effects of a heat-shock protein HSP90 inhibitor 17-allylamino-17-demethoxgeldanamycin (17-AAG) on hepatocellular carcinoma-burdened nude mice.
Methods: CD90+ LCSCs were isolated by magnetic-activated cell sorting from BEL-7404. Spheroid formation, proliferation, differentiation, drug resistance, and tumor formation assays were performed to identify stem cell characteristics. CD90-targeted thermosensitive magnetoliposomes (TMs)-encapsulated 17-AAG (CD90@17-AAG/TMs) was prepared by reverse-phase evaporation and its characteristics were studied. Heat tolerance in CD90+ LCSCs and the effect of CD90@17-AAG/TMs-mediated heat sensitivity were examined in vitro and in vivo.
Results: CD90+ LCSCs showed significant stem cell-like properties. The 17-AAG/TMs were successfully prepared and were spherical in shape with an average size of 128.9±7.7 nm. When exposed to magnetic hyperthermia, HSP90 was up-regulated in CD90+ LCSCs. CD90@17-AAG/TMs inhibited the activity of HSP90 and increased the sensitivity of CD90+ LCSCs to magnetic hyperthermia.
Conclusion: The inhibition of HSP90 could sensitize CD90+ LCSCs to magnetic hyperthermia and enhance its anti-tumor effects in vitro and in vivo.

Keywords: thermoresistance, CD90+ LCSCs, magnetic hyperthermia, 17-AAG

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