title: 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.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  The inhibition of HSP90 could sensitize CD90(+) LCSCs to magnetic hyperthermia and enhance its anti-tumor effects in vitro and in vivo.
authors.affiliation: School of Medicine, Southeast University, Nanjing, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.affiliation: School of Medicine, Southeast University, Nanjing, People's Republic of China.
authors.forename: Qiusha
authors.initials: Q
authors.lastname: Tang
authors.affiliation: School of Medicine, Southeast University, Nanjing, People's Republic of China.
authors.forename: Fengqin
authors.initials: F
authors.lastname: Miao
authors.affiliation: Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Nanjing, People's Republic of China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: An
authors.affiliation: School of Medicine, Southeast University, Nanjing, People's Republic of China.
authors.forename: Mengfei
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Medicine, Southeast University, Nanjing, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Han
authors.affiliation: School of Medicine, Southeast University, Nanjing, People's Republic of China.
authors.forename: Xihui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Infectious Disease, The Third People's Hospital of Nantong, Nangtong, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Medicine, Southeast University, Nanjing, People's Republic of China.
authors.forename: Peidang
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Oncology, Zhongda Hospital, Nangjing, Jiangsu Province, People's Republic of China.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D006979:Hyperthermia, Induced; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology* / Q000628:therapy; D060328:Magnetic Phenomena; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects*
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin
keywords: 17-AAG; CD90+ LCSCs; magnetic hyperthermia; thermoresistance