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 geldanamycinderivate 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. (HEPATOLOGY 2009;50:102-112.)

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

“…Such compounds do not degrade NQO1 but still show HSP90 inhibition (39), and they might be more efficacious with reduced toxicity. It is possible that the benzoquinone moiety binding to mitochondria may explain the liver toxicity of 17AAG observed clinically (5,40,41). Others have shown that tumor cells organize an intramitochondrial HSP90 and TRAP-1 chaperone network and regulate mitochondrial permeability transition (8).…”

“…However, targeting mitochondria could also account for toxicity, e.g., through ROS generation. Because this activity is independent of inhibiting HSP90 chaperone function, diminishing the benzoquinone moiety's toxicity in future drugs should be considered (39,40).…”

Heat Shock Protein 90-Sheltered Overexpression of Insulin-Like Growth Factor 1 Receptor Contributes to Malignancy of Thymic Epithelial Tumors

“…Preparation of total protein lysates from cell cultures as well as subsequent SDS-PAGE and Western immunoblotting was performed as previously described (16). See Supplementary Material for the antibodies employed.…”

Novel Therapeutic Targets for Hepatocellular Carcinoma Treatment

“…Inhibition of a broadspectrum tumorigenic mechanism is resulted when HSP90 is targeted in vitro and in vivo. Independent of the etiological background, all HCC cell lines responded to HSP90 inhibition similarly with increased cell cycle arrest and apoptosis (Breinig et al, 2009). It might due to the fact that HSP90 inhibition triggered a simultaneous degradation of various hepatocarcinogenesis driving factors.…”

“…In vivo studies showed that inhibitor of HSP90 is tumor-cell specific, and is able to efficiently reduce HCC tumor growth. Newly developed HSP90 inhibitor showed a lack of significant hepatotoxicity and is more tolerated, which become more practical in therapeutic treatment (Breinig et al, 2009). HSP90 inhibition further prevents tumor growth by disruption of tumor angiogenesis, as demonstrated by blocking PDGFR-expression in vascular smooth muscle cells and VEGF2 expression on endothelial cells (Lang et al, 2009).…”