Combination therapy of poly (ADP-ribose) polymerase inhibitor 3-aminobenzamide and gemcitabine shows strong antitumor activity in pancreatic cancer cells

J Gastroenterol Hepatol. 2007 May;22(5):738-48. doi: 10.1111/j.1440-1746.2006.04496.x.

Abstract

Background and aim: Poly (ADP-ribose) polymerase (PARP) inhibitors such as 3-aminobenzamide (3-ABA) enhance the in vitro cytotoxicity of DNA mono-functional alkylating agents such as radiation or chemotherapeutic agents. The aim of this study was to test an approach combining the PARP inhibitor 3-ABA with standard gemcitabine therapy in human pancreatic cancer cells.

Methods: Cell viability was determined by proliferation assay (XTT). Cell-cycle analysis (FACS), ELISA (M30 Apoptosense), Western blot for caspase 8 and PARP, and electron microscopy were used to identify apoptosis. Tumor growth and survival was assessed in nude mice by subcutaneously injected Capan-1 cells. In addition, Ki67 staining was performed on tumors for cell proliferation and in vivo apoptosis induction was measured by TUNEL assay and ELISA.

Results: Combination therapy of gemcitabine and 3-ABA suppressed tumor cell growth more than gemcitabine alone in XTT, FACS and ELISA analysis.

Conclusion: This in vivo study demonstrated a significantly reduced tumor weight and increased survival up to 40 days after cell inoculation with combination therapy compared to animals treated with PBS, gemcitabine or 3-ABA alone. Furthermore, TUNEL assay revealed a significant apoptosis induction and reduced proliferation in the combination group.

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Benzamides / administration & dosage
  • Benzamides / pharmacology*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Separation
  • Cell Survival / drug effects
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology*
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gemcitabine
  • Humans
  • In Situ Nick-End Labeling
  • Inhibitory Concentration 50
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / pathology
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Time Factors

Substances

  • Antimetabolites, Antineoplastic
  • Benzamides
  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Deoxycytidine
  • 3-aminobenzamide
  • Poly(ADP-ribose) Polymerases
  • Gemcitabine