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.