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.