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

• Published in: International journal of nanomedicine Vol. 10; no. default; pp. 7345 - 7358
• Main Authors: Yang, Rui, Tang, Qiusha, Miao, Fengqin, An, Yanli, Li, Mengfei, Han, Yong, Wang, Xihui, Wang, Juan, Liu, Peidang, Chen, Rong
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press 07.12.2015
• Subjects: 17-AAG; Animals; Benzoquinones - pharmacology; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; CD90+ LCSCs; Cell Line, Tumor; Female; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Humans; Hyperthermia, Induced; Lactams, Macrocyclic - pharmacology; Liver Neoplasms - pathology; Liver Neoplasms - therapy; magnetic hyperthermia; Magnetic Phenomena; Mice; Mice, Nude; Neoplastic Stem Cells - drug effects; Original Research; thermoresistance; CD90+ LCSCs; 17-AAG; thermoresistance; magnetic hyperthermia
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S93758

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. 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. 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. The inhibition of HSP90 could sensitize CD90(+) LCSCs to magnetic hyperthermia and enhance its anti-tumor effects in vitro and in vivo.