Potent Activity of a Novel Dimeric Heat Shock Protein 90 Inhibitor against Head and Neck Squamous Cell Carcinoma In vitro and In vivo

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone that promotes the conformational maturation of numerous client proteins, many of which play critical roles in tumor cell growth and survival. The ansamycin-based Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in phase I/II clinical testing. However, 17-AAG is difficult to formulate and displays weak activity against some tumors. A novel dimeric ansamycin, EC5, was evaluated for antitumor activity in eight head and neck squamous cell carcinoma (HNSCC) cell lines. Both 17-AAG and EC5 inhibited tumor cell proliferation effectively, but EC5 was more potent, with IC 50 below 200 nmol/L in most cell lines tested, including several lines that were resistant to 17-AAG. The inability of 17-AAG to kill JHU12 cells was linked to a defect in retinoblastoma signaling and could be rescued by ectopic expression of p16 INK4a. EC5 induced G 1 growth arrest of tumor cells and apoptosis, with the degradation of client proteins including epidermal growth factor receptor, c-Raf-1, Akt, and Cdk4 and inhibition of Akt phosphorylation. In vivo, EC5 dramatically reduced the growth rate of established HNSCC xenografts in nude mice and decreased expression of epidermal growth factor receptor and Akt within the xenografts.These results suggest that this novel ansamycin-based Hsp90 inhibitor affects multiple pathways involved in tumor development and progression and may represent a new strategy for the treatment of HNSCC patients.

BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy

“…26,27 We have previously described a novel intraperitoneally administered, ansamycinbased Hsp90 inhibitor, EC5, which effectively inhibited the growth of HNSCC cells in vitro and in in vivo tumor models. 13 Several Hsp90 client proteins including EGFR, ErbB2, Raf-1, vascular epithelial growth factor (VEGF) and protein kinase B (PKB0/Akt) are known to play a role in radiation resistance, [22][23][24] and this positions Hsp90 inhibitors as good candidates for therapeutic radiosensitization.…”

“…These results are in agreement with those reported previously. 13 By contrast, all 4 cell lines were more sensitive to BIIB021, with the mean IC 50 of 250 6 100 nM, falling within a more restricted range (Fig. 2a).…”

“…13 Cal27 is sensitive to both cisplatin and radiation, while UM11B is relatively resistant to both therapies. In contrast, JHU12 and JHU22 are resistant to cisplatin whilst relative sensitive to radiation.…”

“…[10][11][12] We and others have previously demonstrated that inhibition of Hsp90 causes degradation of these proteins and enhances tumor cell death in a variety of cell lines and tumor models, including HNSCC. [13][14][15] All these evidences indicate that inhibition of Hsp90 may not only provide a unique therapeutic pathway, but also promote the therapeutic effect of a variety of existing antitumor agents. Several Hsp90 inhibitors are currently under clinical investigation in a variety of oncology indications, spearheaded by 17-allylamino-17-demethoxygeldanamycin (17-AAG), a geldanamycin (GA) derivative.…”

Network-based analysis of calcium-binding protein genes identifies Grp94 as a target in human oral carcinogenesis

“…Considerable evidence has shown a significant association between the heat-shock protein 90 (Hsp90) and a wide range of human malignancies, including head and neck cancers (Ito et al, 1998;Baker et al, 2005;Yin et al, 2005). Grp94, also known as gp96, is the ER-resident member of the Hsp90 family constitutively expressed in virtually all cell types (Van et al, 1989) and the most abundant ER chaperon protein showing high homology (50%) to cytosolic counterpart Hsp90 (Sorger and Pelham, 1987).…”