Targeting heat shock protein 90 with non-quinone inhibitors: A novel chemotherapeutic approach in human hepatocellular carcinoma Journal Article


Authors: Breinig, M.; Caldas-Lopes, E.; Goeppert, B.; Malz, M.; Rieker, R.; Bergmann, F.; Schirmacher, P.; Mayer, M.; Chiosis, G.; Kern, M. A.
Article Title: Targeting heat shock protein 90 with non-quinone inhibitors: A novel chemotherapeutic approach in human hepatocellular carcinoma
Abstract: The inhibition of heat shock protein 90 (Hsp90) has emerged as a promising antineoplastic strategy in diverse human malignancies. Hsp90 has been predicted to be involved in hepatocellular carcinoma (HCC) development; however, its role in hepatocarcinogenesis remains elusive. Using chemically distinctive Hsp90 inhibitors, we show that Hsp90 capacitates the aberrant expression and activity of crucial hepatocarcinogenesis-driving factors (e.g., insulin-like growth factor receptor 1, hepatocyte growth factor receptor, protein kinase B, v-raf-1 murine leukemia viral oncogene homolog 1, and cyclin-dependent kinase 4). In vitro, Hsp90 inhibition with both geldanamycin analogs (17-allylamino-17- desmethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17- desmethoxygeldanamycin (17-DMAG)) and the non-quinone compound 8-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl) -9H-purin-6-amine (PU-H71) reduced the viability of various HCC cell lines, induced the simultaneous degradation of numerous hepatocarcinogenic factors, and caused substantial cell cycle arrest and apoptosis. In contrast, nontumorigenic hepatocytes were less susceptible to Hsp90 inhibition. Because conventional geldanamycin-derivate Hsp90 inhibitors induce dose-limiting liver toxicity, we tested whether novel Hsp90 inhibitors lacking the benzoquinone moiety, which has been deemed responsible for hepatotoxicity, can elicit antineoplastic activity without causing significant liver damage. In HCC xenograft mouse models, PU-H71 was retained in tumors at pharmacologically relevant concentrations while being rapidly cleared from nontumorous liver. PU-H71 showed potent and prolonged in vivo Hsp90 inhibitory activity and reduced tumor growth without causing toxicity. Conclusion: Hsp90 constitutes a promising therapeutic target in HCC. Non-quinone Hsp90 inhibitors exhibit tumor-specific accumulation and exert potent antineoplastic activity without causing significant hepatotoxicity. Copyright © 2009 by the American Association for the Study of Liver Diseases.
Keywords: controlled study; unclassified drug; human cell; liver cell carcinoma; nonhuman; carcinoma, hepatocellular; liver neoplasms; drug targeting; mouse; animal; animals; mice; animal tissue; apoptosis; animal experiment; animal model; antineoplastic activity; cancer cell culture; tumor xenograft; tumor cell culture; tumor cells, cultured; drug antagonism; liver tumor; 17 demethoxy 17 (2 dimethylaminoethylamino)geldanamycin; 8 (6 iodobenzo[d][1,3]dioxol 5 ylthio) 9 [3 (isopropylamino)propyl] 9h purin 6 amine; heat shock protein 90 inhibitor; pu h71; tanespimycin; heat shock protein 90; quinone derivative; cell cycle arrest; drug clearance; single drug dose; toxicity testing; hsp90 heat-shock proteins; quinones
Journal Title: Hepatology
Volume: 50
Issue: 1
ISSN: 0270-9139
Publisher: John Wiley & Sons  
Date Published: 2009-07-01
Start Page: 102
End Page: 112
Language: English
DOI: 10.1002/hep.22912
PUBMED: 19441108
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 7" - "Export Date: 30 November 2010" - "CODEN: HPTLD" - "Source: Scopus"
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Gabriela Chiosis
    279 Chiosis