Nitric oxide-donating aspirin derivatives suppress microsatellite instability in mismatch repair-deficient and hereditary nonpolyposis colorectal cancer cells.

Abstract

Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are an emergent class of pharmaceutical derivatives with promising utility as cancer chemopreventive agents. Aspirin and sulindac have been shown to be effective in selecting for cells with reduced microsatellite instability (MSI) that is inherent in mismatch repair (MMR)-deficient hereditary nonpolyposis colorectal cancer (HNPCC) cells. The effect of NO-NSAIDs on MSI in MMR-deficient HNPCC cells is unknown. Here, we have examined genetically defined MMR-deficient murine embryo fibroblasts, murine colonocytes, and isogenic human HNPCC tumor cell lines treated with acetylsalicylic acid (aspirin; ASA) and three isomeric derivatives of NO-aspirin (NO-ASA). The MSI profiles were determined and compared with the Bethesda Criteria. We found that the ASA- and NO-ASA-treated MMR-deficient cell lines displayed a dose-dependent suppression of MSI that appeared as early as 8 weeks and gradually increased to include up to 67% of the microsatellite sequences examined after 19 to 20 weeks of continuous treatment. Residual resistance to microsatellite stabilization was largely confined to mononucleotide repeat sequences. Control (MMR-proficient) cells showed no changes in microsatellite status with or without treatment. The relative dose-dependent stabilization selection was: ortho-NO-ASA approximately para-NO-ASA > meta-NO-ASA >> ASA. Moreover, the doses required for stabilization by the ortho- and para-NO-ASA were 300- to 3,000-fold lower than ASA. These results suggest that NO-ASA derivatives may be more effective at suppressing MSI in MMR-deficient cell lines than ASA and should be considered for chemopreventive trials with HNPCC carriers.

• Authors: Michael A McIlhatton, Jessica Tyler, Susan Burkholder, Josef Ruschoff, Basil Rigas, Levy Kopelovich, Richard Fishel
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 22 Pg. 10966-75 (Nov 15 2007) ISSN: 1538-7445 [Electronic] United States
• PMID: 18006842 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Nitric Oxide
• Aspirin

Topics

• Animals
• Aspirin (pharmacology)
• Base Pair Mismatch
• Cell Line, Tumor
• Colon (metabolism)
• Colorectal Neoplasms, Hereditary Nonpolyposis (drug therapy, genetics)
• DNA Repair
• Dose-Response Relationship, Drug
• Fibroblasts (metabolism)
• Humans
• Inhibitory Concentration 50
• Mice
• Microsatellite Instability
• Microsatellite Repeats
• Nitric Oxide (metabolism)