Article

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

Department of Molecular Virology, Immunology & Medical Genetics, Ohio State University, Columbus, OH 43210, USA.
Cancer Prevention Research (Impact Factor: 4.44). 03/2011; 4(5):684-93. DOI: 10.1158/1940-6207.CAPR-10-0319
Source: PubMed

ABSTRACT

Nonsteroidal anti-inflammatory drugs (NSAID) appear to be effective cancer chemopreventives. Previous cellular studies showed 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 nonpolyposis colorectal cancer or Lynch syndrome (LS/HNPCC), at doses 300- to 3,000-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% to 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 (720/1,500 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, as low-dose NO-ASA shows 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.

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    • "Previously published data on low-dose ASA administration in mice with intestinal or other tumors used doses of 40 mg/kg [42] and 50 mg/kg [43]. High-dose ASA dosage was at 400 mg/kg in a previous tumor prevention study in mice [44]. Two studies in intestinal tumor models used a dose of 25 mg/kg [45, 46], which the authors calculated to correspond to a dose of 80–110 mg/day in humans on a 2000 kcal diet following nutrient density calculations [47], and we decided to use this dose in our experiment to mimic low-dose ASA administration. "
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    ABSTRACT: The role of non-steroidal anti-inflammatory drugs in inflammatory bowel disease is controversial, as they have been implicated in disease aggravation. Different from other cyclooxygenase inhibitors, acetylsalicylic acid (ASA) enhances the formation of anti-inflammatory and proresolution lipoxins derived from arachidonic acid as well as resolvins from omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). In this study, we examined the effect of ASA on murine dextran sodium sulfate colitis. A mouse magnetic resonance imaging (MRI) protocol and post mortem assessment were used to assess disease severity, and lipid metabolites were measured using liquid chromatography-coupled tandem mass spectrometry. Decreased colitis activity was demonstrated by phenotype and MRI assessment in mice treated with ASA, and confirmed in postmortem analysis. Analysis of lipid mediators showed sustained formation of lipoxin A4 and an increase of DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA) after treatment with ASA. Furthermore, in vitro experiments in RAW264.7 murine macrophages demonstrated significantly increased phagocytosis activity after incubation with 17-HDHA, supporting its proresolution effect. These results show a protective effect of ASA in a murine colitis model and could give a rationale for a careful reassessment of ASA therapy in patients with inflammatory bowel disease and particularly ulcerative colitis, possibly combined with DHA supplementation.
    Full-text · Article · Sep 2013
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    • "Recently, in a mouse model of HNPCC, McIlhatton et al., reported that aspirin and low dose NO-aspirin increased life span. However, though the intestinal tumours in aspirin treated animals showed less microsatellite instability, low dose NO-aspirin had 'minimal effect on MSI status' and high dose NO-aspirin decreased life span and increased MSI (McIlhatton et al., 2011). In addition to the phenomenon of aspirin selecting for microsatellite stability in colorectal cancer cells (Ruschoff et al., 1998), aspirin in vitro can inhibit CRC growth and increase the level of the DNA MMR proteins hMLH1, hMSH2, hMSH6 and hPMS2 in DNA MMR proficient cells (Goel et al., 2003). "

    Full-text · Dataset · Mar 2013
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    • "Recently, in a mouse model of HNPCC, McIlhatton et al., reported that aspirin and low dose NO-aspirin increased life span. However, though the intestinal tumours in aspirin treated animals showed less microsatellite instability, low dose NO-aspirin had 'minimal effect on MSI status' and high dose NO-aspirin decreased life span and increased MSI (McIlhatton et al., 2011). In addition to the phenomenon of aspirin selecting for microsatellite stability in colorectal cancer cells (Ruschoff et al., 1998), aspirin in vitro can inhibit CRC growth and increase the level of the DNA MMR proteins hMLH1, hMSH2, hMSH6 and hPMS2 in DNA MMR proficient cells (Goel et al., 2003). "

    Full-text · Chapter · Oct 2011
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