Inhibitor of heat-shock protein 90 enhances the antitumor effect of DNA vaccine targeting clients of heat-shock protein.
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.
Lin
Chi-Chen
CC
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
Tu
Cheng-Fen
CF
Yen
Meng-Chi
MC
Chen
Ming-Chuan
MC
Hsieh
Wan-Jung
WJ
Chang
Wen-Chang
WC
Chang
Wen-Tsang
WT
Lai
Ming-Derg
MD
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D019444:Vaccines, DNA / Q000494:pharmacology*
D016227:Benzoquinones; D019496:Cancer Vaccines; D016207:Cytokines; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D019444:Vaccines, DNA; C001277:geldanamycin