Inhibitor of heat-shock protein 90 enhances the antitumor effect of DNA vaccine targeting clients of heat-shock protein

Mol Ther. 2007 Feb;15(2):404-10. doi: 10.1038/


Geldanamycin (GA), a heat-shock protein (HSP) 90 inhibitor, induces degradation of HSP90 client proteins, which may promote the presentation of degradation peptides with major histocompatibility complex class I on cancer cells. We hypothesized that GA may enhance the efficacy of DNA vaccination, and investigated the therapeutic effect of the combination of GA and a DNA vaccine against HSP90 clients p185(neu) and Met. The efficacy of various doses of GA combined with an N-terminal neu (N'-neu) DNA vaccine was investigated in a transplanted tumor constitutively overexpressing endogenous p185(neu). Low-dose (2.5 mug) but not high-dose (10 microg) GA enhanced the effect of N'-neu DNA vaccination on the inhibition of murine bladder tumor-2 tumors in syngeneic C3H mice. Anti-p185(neu) antibody titers were similar among all treated groups. Significantly increased infiltrations of CD8(+) T cells and NK cells were observed at tumor sites. GA sensitized tumor cells to the cytotoxic effects of lymphocytes. Depletion of CD8(+) T cells eliminated most of the therapeutic efficacy; in contrast, depletion of CD4(+) T cells enhanced the therapeutic efficacy. A similar enhancing effect was observed for the combination of GA and a DNA vaccine targeting the Met oncogene. Our results support the use of combination of GA and DNA vaccination against GA-targeted proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoquinones / pharmacology*
  • Blotting, Western
  • Cancer Vaccines / immunology
  • Cancer Vaccines / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cytokines / analysis
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / immunology
  • Lactams, Macrocyclic / pharmacology*
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / prevention & control*
  • Survival Analysis
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Vaccines, DNA / pharmacology*


  • Benzoquinones
  • Cancer Vaccines
  • Cytokines
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Vaccines, DNA
  • geldanamycin