Carcinogenesis Advance Access originally published online on November 2, 2005
Carcinogenesis 2006 27(4):803-810; doi:10.1093/carcin/bgi262
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NO-donating aspirin induces phase II enzymes in vitro and in vivo
Division of Cancer Prevention, Department of Medicine, SUNY at Stony Brook, NY 11794, USA and 1 Department of Physiology and Pharmacology, City University of New York Medical School, New York, NY 10031, USA
* To whom correspondence should be addressed at: Division of Cancer Prevention, Department of Medicine, Life Sciences Building 06, SUNY at Stony Brook, Stony Brook, NY 11794-5200, USA. Tel: +1 631 632 9035; Fax: +1 631 632 1992; Email: basil.rigas{at}sunysb.edu
Modulation of drug metabolizing enzymes, leading to facilitated elimination of carcinogens represents a successful strategy for cancer chemoprevention. Nitric oxide-donating aspirin (NO-ASA) is a promising agent for the prevention of colon and other cancers. We studied the effect of NO-ASA on drug metabolizing enzymes in HT-29 human colon adenocarcinoma and Hepa 1c1c7 mouse liver adenocarcinoma cells and in Min mice treated with NO-ASA for 3 weeks. In these cell lines, NO-ASA induced the activity and expression of NAD(P)H:quinone oxireductase (NQO) and glutathione S-transferase (GST). Compared with untreated Min mice, NO-ASA increased in the liver the activity (nmol/min/mg; mean ± SEM for all) of NQO (85 ± 6 versus 128 ± 11, P<0.05) and GST (2560 ± 233 versus 4254 ± 608, P < 0.005) and also in the intestine but not in the kidney; the expression of NQO1 and GST P1-1 was also increased. NO-ASA had only a marginal effect on P450 1A1 and P450 2E1, two phase I enzymes. The release of NO from NO-ASA, determined with a selective microelectrode was paralleled by the induction of NQO1 and abrogated by NO scavengers; an exogenous NO donor also induced the expression of NQO1. NO-ASA induced concentration-dependently the translocation of Nrf2 into the nucleus as documented by immunofluorescence and immunoblotting; this paralleled the induction of NQO1 and GST P1-1. Thus NO-ASA induces phase II enzymes, at least in part, through the action of NO that it releases and by modulating the Keap1–Nrf2 pathway; this effect may be part of its mechanism of action against colon and other cancers.
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