Improvement of replication fidelity by certain mesalazine derivatives

Int J Oncol. 2012 May;40(5):1331-8. doi: 10.3892/ijo.2012.1381. Epub 2012 Feb 21.

Abstract

Epidemiological evidence on the chemopreventive activity of mesalazine against colitis-associated cancer has accumulated in recent years. Together with the variety of mesalazine molecular antitumor effects this has prompted the development of novel mesalazine derivatives. The objective of this study was to test five novel derivatives (compounds 2-14, 2-17, 2-28, 2-34L, 2-39) for their effect on cell proliferation, their capability to scavenge superoxide anions, to induce a cell cycle arrest and to improve replication fidelity in cultured colorectal cells. Compound 2-14 was identified as the strongest inhibitor of cell proliferation and functioned as a potent superoxide scavenger, as did 2-17 and 2-34L. 2-14 induced a G2/M-arrest in HCT116 and a G0/G1-arrest in HT29 cells. 2-17 caused a G0/G1-arrest and 2-34L a G2/M-arrest in HT29 cells. 2-17 and 2-34L reduced mutation rates at a (CA)13 repeat in a dose-dependent fashion. These data suggest that certain mesalazine derivatives share important antitumor effects. From this experimental profile compounds 2-17 and 2-34L both improve replication fidelity, which is biologically relevant not only for colitis-associated cancer but also potentially for individuals with hereditary non-polyposis colorectal cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Anticarcinogenic Agents / pharmacology*
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation / drug effects
  • Checkpoint Kinase 1
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / prevention & control*
  • DNA Replication / drug effects*
  • Dose-Response Relationship, Drug
  • Free Radical Scavengers / pharmacology
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Mesalamine / pharmacology*
  • MutL Protein Homolog 1
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oxidative Stress / drug effects
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects
  • Superoxides / metabolism
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Anticarcinogenic Agents
  • Cell Cycle Proteins
  • Free Radical Scavengers
  • MLH1 protein, human
  • Nuclear Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Superoxides
  • Mesalamine
  • Protein Kinases
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Checkpoint Kinase 1
  • Protein-Serine-Threonine Kinases
  • MutL Protein Homolog 1