Histone deacetylase inhibitor trichostatin A and proteasome inhibitor PS-341 synergistically induce apoptosis in pancreatic cancer cells

Biochem Biophys Res Commun. 2006 Oct 6;348(4):1245-53. doi: 10.1016/j.bbrc.2006.07.185. Epub 2006 Aug 7.

Abstract

Pancreatic cancer is a common and lethal malignancy. Pancreatic cancer cells overexpress multiple anti-apoptotic factors and death receptor decoys, and are strongly resistant to radiation and to 5-fluorouracil (5-FU)- or gemcitabine (Gem)-based chemotherapy regimens. We have found that low-dose proteasome inhibitor PS-341 and histone deacetylase inhibitor trichostatin A (TSA) synergistically induce cytotoxicity in a panel of eight diverse pancreatic cancer cell lines. Combining TSA with PS-341 effectively inactivated NFkappaB signaling, downregulated the predominant endogenous anti-apoptotic factor Bcl-XL overexpression, and disrupted MAP kinase pathway. The combined drug regimen effectively inflicted an average of 71.5% apoptotic cell death (55.2-80%) in diverse pancreatic cancer cell lines by activating the intrinsic apoptotic pathway.

Conclusion: The TSA/PS-341 regimen may represent a potential novel therapeutic strategy for pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / toxicity*
  • Apoptosis*
  • Boronic Acids / toxicity*
  • Bortezomib
  • Caspases / metabolism
  • Cell Line, Tumor
  • Drug Synergism
  • Enzyme Inhibitors / toxicity
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / toxicity*
  • NF-kappa B / antagonists & inhibitors
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protease Inhibitors / toxicity
  • Proteasome Inhibitors*
  • Pyrazines / toxicity*
  • bcl-X Protein / metabolism

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • NF-kappa B
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Pyrazines
  • bcl-X Protein
  • trichostatin A
  • Bortezomib
  • Poly(ADP-ribose) Polymerases
  • Caspases