Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin

Abstract

Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation and may consequently serve as a therapeutic target for the treatment of oesophageal cancer for which adequate therapy is often lacking. We studied the expression of Hsp90 in tumour tissues of human oesophageal cancer and the impact of Hsp90 inhibition on oesophageal cancer cell lines using the drug 17-allylamino-17-demethoxygeldanamycin (17-AAG). Quantitative immunohistochemistry was performed on formalin-fixed paraffin-embedded tissues from patients with oesophageal cancer. In squamous cell carcinoma, a marked upregulation of Hsp90 could be noted in dysplastic epithelium and invasive cancer compared with normal epithelium. In adenocarcinoma, Hsp90 was expressed in neoplastic epithelium and also in normal non-neoplastic glands weakly. The inhibition of Hsp90 using 17-AAG led to a significant decrease in cell proliferation and viability in human oesophageal cancer cell lines. Using a clonogenic cell survival assay, Hsp90 inhibition significantly sensitised the cells for g-photon irradiation. Heat shock protein 90 was found to be critical for proper signalling induced by both epidermal growth factor and insulin-like growth factor-1, in which the inhibition of signalling by 17-AAG correlated with the observed reduction in cell proliferation and viability. These results showed that Hsp90 was selectively expressed in oesophageal cancer tissue compared with the corresponding normal tissue, and the inhibition of Hsp90 resulted in decreased proliferation and viability as well as radiosensitisation of oesophageal cancer cells. Heat shock protein 90 represents a potential therapeutic target in the treatment of patients with oesophageal cancer, alone or in combination with radiotherapy.

Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors

“…Similar findings have been obtained in other tumor cells, e.g. derived from hepatocellular carcinoma ), breast cancer (Caldas-Lopes et al 2009), monocytic leukemia (Peng et al 2010), and esophageal cancer (Wu et al 2009). Thus, HSP90 is likely to protect the function of these oncogenic factors in PET and thereby acts in a protumorigenic manner.…”

Novel HSP90 inhibitors, NVP-AUY922 and NVP-BEP800, radiosensitise tumour cells through cell-cycle impairment, increased DNA damage and repair protraction

“…Indeed, a number of studies have already explored Hsp90 as a potential molecular target for radiosensitisation of tumour cells (Bisht et al, 2003;Machida et al, 2003;Russell et al, 2003;Bull et al, 2004;Harashima et al, 2005;Dote et al, 2006;Kabakov et al, 2008;Wu et al, 2009). Thus, the inhibitor of Hsp90, geldanamycin, and its derivatives significantly enhance the radiosensitivity of tumour cell lines derived from a variety of histologies, including glioma, prostate, pancreas and cervix (Bisht et al, 2003;Enmon et al, 2003;Machida et al, 2003;Russell et al, 2003;Bull et al, 2004;Harashima et al, 2005;Dote et al, 2006).…”

Hsp90 Inhibitor Geldanamycin Enhances the Antitumor Efficacy of Enediyne Lidamycin in Association with Reduced DNA Damage Repair

“…However, in HepG2 cells the circumstance was Hsp90 Inhibitor Geldanamycin Enhances Antitumor Efficacy of Enediyne Lidamycin with Reduced DNA Damage Repair drugs and IR (Pelicano et al, 2006;McCollum et al, 2008;Sawai et al, 2008;Watanabe et al, 2008;Wu et al, 2009). In this study, we have shown that the potent cytotoxicity of LDM was enhanced by Hsp90 inhibitor, GDM.…”