Mesalazine causes a mitotic arrest and induces caspase-dependent apoptosis in colon carcinoma cells.
Non-steroidal anti-inflammatory drugs (NSAID) may inhibit colon cancer development through affecting proliferation and apoptosis. However, their use in cancer chemoprevention is still limited due to toxicities. There is longstanding clinical experience with the aminosalicylate mesalazine in the treatment of patients with inflammatory bowel disease with very few side effects. So far, most studies on the cellular effects of mesalazine were focused on its anti-inflammatory properties. Recent data, however, indicate that mesalazine may also reduce cell growth in vivo. We therefore investigated the growth inhibitory effect of mesalazine on human colon cancer cells in vitro compared with established chemopreventive agents. We also wished to determine the underlying cellular mechanisms of the effect. Here we show that mesalazine dose- and time-dependently inhibited the proliferation of colon cancer cells. Mesalazine was less potent in reducing cell growth than sulindac sulfide or indomethacin but growth effective mesalazine concentrations were comparable with concentrations achievable in vivo under standard mesalazine treatment. While other NSAID induced a robust G(1) arrest, mesalazine specifically blocked cells in mitosis although microtubule polymerization or spindle orientation was not affected. In addition, mesalazine induced apoptosis in colon cancer cells possibly through activation of caspase-3 whereas the levels of bcl-2 family proteins were not altered. We conclude that mesalazine inhibits growth of colon cancer cells largely through a mitotic arrest, which has not been reported for NSAID so far. Mesalazine also induces apoptosis through partial activation of caspases similar to, although weaker than, established chemopreventive agents. These findings may suggest a potential of mesalazine as a chemopreventive agent for colorectal cancer.
Reinacher-Schick
A
A
Department of Medicine, Ruhr-University Bochum, Knappschaftskrankenhaus, Germany. wolff.schmiegel@ruhr-uni-bochum.de
Schoeneck
A
A
Graeven
U
U
Schwarte-Waldhoff
I
I
Schmiegel
W
W
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D016195:G2 Phase / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D019804:Mesalamine / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine; D020169:Caspases