Inhibition of ADP ribosylation prevents and cures helicobacter-induced gastric preneoplasia

Cancer Res. 2010 Jul 15;70(14):5912-22. doi: 10.1158/0008-5472.CAN-10-0528.


Gastric adenocarcinoma develops as a consequence of chronic inflammation of the stomach lining that is caused by persistent infection with the bacterium Helicobacter pylori. Gastric carcinogenesis progresses through a sequence of preneoplastic lesions that manifest histologically as atrophic gastritis, intestinal metaplasia, and dysplasia. We show here in several preclinical models of Helicobacter-induced atrophic gastritis, epithelial hyperplasia, and metaplasia that the inhibition of ADP ribosylation by the small-molecule inhibitor PJ34 not only prevents the formation of gastric cancer precursor lesions, but also efficiently reverses preexisting lesions. PJ34 exerts its chemopreventive and therapeutic effects by impairing Helicobacter-specific T-cell priming and T(H)1 polarization in the gut-draining mesenteric lymph nodes. The subsequent infiltration of pathogenic T cells into the gastric mucosa and the ensuing gastric T cell-driven immunopathology are prevented efficiently by PJ34. Our data indicate that PJ34 directly suppresses T-cell effector functions by blocking the IFN-gamma production of mesenteric lymph node T cells ex vivo. Upon exposure to PJ34, purified T cells failed to synthesize ADP-ribose polymers and to activate the transcription of genes encoding IFN-gamma, interleukin 2, and the interleukin 2 receptor alpha chain in response to stimuli such as CD3/CD28 cross-linking or phorbol 12-myristate 13-acetate/ionomycin. The immunosuppressive and chemoprotective effects of PJ34 therefore result from impaired T-cell activation and T(H)1 polarization, and lead to the protection from preneoplastic gastric immunopathology. In conclusion, ADP-ribosylating enzymes constitute novel targets for the treatment of Helicobacter-associated gastric lesions predisposing infected individuals to gastric cancer and may also hold promise for the treatment of other T cell-driven chronic inflammatory conditions and autoimmune pathologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / antagonists & inhibitors
  • Adenosine Diphosphate / immunology
  • Adenosine Diphosphate / metabolism
  • Animals
  • Gastritis, Atrophic / drug therapy*
  • Gastritis, Atrophic / immunology
  • Gastritis, Atrophic / microbiology
  • Helicobacter Infections / drug therapy*
  • Helicobacter Infections / immunology
  • Helicobacter pylori / growth & development*
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interleukin-2 / antagonists & inhibitors
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / genetics
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phenanthrenes / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Precancerous Conditions / drug therapy*
  • Precancerous Conditions / immunology
  • Precancerous Conditions / microbiology
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / immunology
  • Stomach Neoplasms / microbiology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism


  • Interleukin-2
  • N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
  • Phenanthrenes
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Adenosine Diphosphate
  • Interferon-gamma