Zoledronic Acid Has Direct Antiproliferative and Antimetastatic Effect on Pancreatic Carcinoma Cells and Acts as an Antigen for delta2 gamma/delta T Cells

J Immunother. May-Jun 2007;30(4):370-7. doi: 10.1097/CJI.0b013e31802bff16.

Abstract

Beside their use as antiresorptive drug, bisphosphonates are well known to stimulate gammadelta T cells and to have direct effects on tumor growth. We determined the direct cytotoxic potential, induction of apoptosis, and antimigratory effect of zoledronic acid. The susceptibility of pancreatic carcinoma cells pretreated with bisphosphonates against gammadelta T cells was tested and the subgroup involved in killing was determined. Zoledronic acid has a cytotoxic potential even at pharmacologic dosage. Zoledronic acid does not only induce apoptosis by inhibiting the Ras-pathway but has also an antimetastatic effect as shown in migration assays and by down-regulation of urokinase plasminogen activator. Freshly prepared gammadelta T cells consisting mainly of Vdelta2 cells showed increased cytotoxicity against bisphosphonate-treated pancreatic carcinoma cells. Our results demonstrate that zoledronic acid has a direct apoptotic effect on pancreatic carcinoma cells and has antimigratory properties. Tumor cells treated with zoledronic acid are more vulnerable against Vgamma9 Vdelta2 T cell attack. Treatment with zoledronic acid for patients with pancreatic carcinoma might be an option.

MeSH terms

  • Adenocarcinoma / pathology
  • Apoptosis
  • Bone Density Conservation Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Diphosphonates / pharmacology*
  • Flow Cytometry
  • Humans
  • Imidazoles / pharmacology*
  • Immunoblotting
  • Neoplasm Invasiveness
  • Neoplasm Metastasis / drug therapy*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Tetrazolium Salts / pharmacology
  • Thiazoles / pharmacology
  • Zoledronic Acid

Substances

  • Bone Density Conservation Agents
  • Diphosphonates
  • Imidazoles
  • Tetrazolium Salts
  • Thiazoles
  • Zoledronic Acid
  • thiazolyl blue