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

Chi Chen Lin, Cheng Fen Tu, Meng Chi Yen, Ming Chuan Chen, Wan Jung Hsieh, Wen Chang Chang, Wen Tsang Chang, Ming Derg Lai

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

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 p185neu 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 p185neu. Low-dose (2.5μg) but not high-dose (10μg) GA enhanced the effect of N′-neu DNA vaccination on the inhibition of murine bladder tumor-2 tumors in syngeneic C3H mice. Anti-p185neu 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.

Original languageEnglish
Pages (from-to)404-410
Number of pages7
JournalMolecular Therapy
Volume15
Issue number2
DOIs
Publication statusPublished - Feb 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology

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