Aspirin and Low-Dose Nitric Oxide–Donating Aspirin Increase Life Span in a Lynch Syndrome Mouse Model

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) appear to be effective cancer chemopreventives. Previous cellular studies demonstrated that aspirin (acetylsalicylic acid: ASA) and nitric oxide-donating ASA (NO-ASA) suppressed microsatellite instability (MSI) in mismatch repair (MMR)-deficient cells linked to the common cancer predisposition syndrome hereditary non-polyposis colorectal cancer or Lynch syndrome (LS/HNPCC), at doses 300-3000-fold less than ASA. Using a mouse model that develops MMR-deficient intestinal tumors that appear pathologically identical to LS/HNPCC we show that ASA (400 mg/kg) and low dose NO-ASA (72 mg/kg) increased life span by 18–21%. We also note a trend where ASA treatment resulted in intestinal tumors with reduced high MSI (H-MSI) and increased low MSI (L-MSI) as defined by the Bethesda Criteria. Low dose NO-ASA had a minimal effect on MSI status. In contrast to previous studies, high dose NO-ASA (720/1500 mg/kg) treatments increased tumor burden, decreased life span and exacerbated MSI uniquely in the LS/HNPCC mouse model. These results suggest that MMR-deficient tissues/mice may be specifically sensitive to intrinsic pharmacokinetic features of this drug. It is likely that long-term treatment with ASA may represent a chemopreventive option for LS/HNPCC patients. Moreover, since low dose NO-ASA demonstrates equivalent life span increase at 10-fold lower doses than ASA, it may have the potential to significantly reduce the gastropathy associated with long-term ASA treatment.