Potent activity of a novel dimeric heat shock protein 90 inhibitor against head and neck squamous cell carcinoma in vitro and in vivo.

نویسندگان

  • Xiaoying Yin
  • Hong Zhang
  • Francis Burrows
  • Lin Zhang
  • Carol G Shores
چکیده

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.

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عنوان ژورنال:
  • Clinical cancer research : an official journal of the American Association for Cancer Research

دوره 11 10  شماره 

صفحات  -

تاریخ انتشار 2005