Chemoprevention of pancreatic cancer: characterization of Par-4 and its modulation by 3,3' diindolylmethane (DIM)

Pharm Res. 2008 Sep;25(9):2117-24. doi: 10.1007/s11095-008-9581-8. Epub 2008 Apr 22.

Abstract

Purpose: Cancer chemoprevention is defined as the use of natural, synthetic, or biological agents to suppress, reverse or prevent the carcinogenic process from turning into aggressive cancer. Prostate apoptosis response-4 (Par-4) is a unique pro-apoptotic protein that selectively induces apoptosis in prostate cancer cells. However, its role in other malignancies has not been fully explored. This study tries to identify the functional significance of Par-4 in pancreatic cancer.

Methods: Multiple molecular techniques such as Western blot analysis, trypan blue assay for cell viability, MTT assay for cell growth inhibition and Histone/DNA ELISA for apoptosis were used.

Results: Western blot analysis revealed that 3,3'-diindolylmethane (DIM) a chemopreventive agent, specifically its more bioavailable formulation, B-DIM, at low doses (20 micromol/L) induces Par-4, in L3.6pl and Colo-357 pancreatic cancer cells. At similar doses, DIM reduced cell viability and caused cell growth inhibition and apoptosis. Moreover, DIM pre-treatment sensitized the cells to cytotoxic action of chemotherapeutic drug gemcitabine through up-regulation of Par-4.

Conclusion: The induction of Par-4 is indirectly related to increased sensitivity and cell death through apoptosis. To our knowledge the results reported here showed, for the first time, the induction of Par-4 by chemopreventive agents, in general, and DIM, in particular, in pancreatic cancer cells in vitro.

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Drug Synergism
  • Humans
  • Indoles / pharmacology*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / prevention & control*
  • Receptors, Thrombin / metabolism*
  • Signal Transduction / drug effects
  • Up-Regulation

Substances

  • Anticarcinogenic Agents
  • Antineoplastic Agents
  • Indoles
  • Receptors, Thrombin
  • Deoxycytidine
  • gemcitabine
  • protease-activated receptor 4
  • Cisplatin
  • 3,3'-diindolylmethane