Inhibition of neuroblastoma xenograft growth by Hsp90 inhibitors.
BACKGROUND
Advanced-stage neuroblastomas are often resistant to chemotherapy. Heat shock protein (Hsp) 90 is a molecular chaperone that maintains the stability of important signal transduction proteins. We have previously reported that geldanamycin (GA), an Hsp90 inhibitor, decreases Raf-1 and Akt protein expressions and induces apoptosis in neuroblastoma cells. We sought to determine the in vivo effects of Hsp90 inhibitor compounds on human neuroblastomas.


METHODS
Human neuroblastoma (LAN-1 and SK-N-SH) xenografts (4-mm3 tumor implants) were placed in the flanks of athymic nude mice. The mice received either Hsp90 inhibitors (17-AAG or EC5) or vehicle (control). The tumor dimensions were measured twice weekly. Proteins were extracted for Western immunoblotting.


RESULTS
Hsp90 inhibitor compounds significantly blocked both LAN-1 and SK-N-SH neuroblastoma growth in vivo. Drug-treated tumors showed decreases in Raf-1 and cleaved PARP expressions.


CONCLUSIONS
Hsp90 inhibitors may prove to be important novel therapeutic agents for patients with advanced-stage neuroblastoma who fail to respond to current treatment regimens.
Kang
Junghee
J
Department of Surgery, The University of Texas Medical Branch, Galveston, TX 7755, USA.
Kamal
Adeela
A
Burrows
Francis J
FJ
Evers
B Mark
BM
Chung
Dai H
DH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D016227:Benzoquinones; C502977:EC5 compound; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin