Improvement of replication fidelity by certain mesalazine derivatives

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.