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Research Articles

Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo

¹ Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago and ² Department of Medicine, University of Illinois at Chicago and Chicago Veterans Administration Medical Center (West Side Division), Chicago, Illinois

Requests for reprints: Gregory R. Thatcher, Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S Wood Street, Chicago, IL 60612. Phone: 312-355-5282. E-mail: thatcher{at}uic.edu

Abstract

Chemopreventive agents in colorectal cancer possess either antiproliferative or anti-inflammatory actions. Nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 inhibitors have shown promise, but are compromised by side effects. Nitric oxide donor NSAIDs are organic nitrates conjugated via a labile linker to an NSAID, originally designed for use in pain relief, that have shown efficacy in colorectal cancer chemoprevention. The NO chimera, GT-094, is a novel nitrate containing an NSAID and disulfide pharmacophores, a lead compound for the design of agents specifically for colorectal cancer. GT-094 is the first nitrate reported to reduce aberrant crypt foci (by 45%) when administered after carcinogen in the standard azoxymethane rat model of colorectal cancer. Analysis of proximal and distal colon tissue from 8- and 28-week rat/azoxymethane studies showed that GT-094 treatment reduced colon crypt proliferation by 30% to 69%, reduced inducible NO synthase (iNOS) levels by 33% to 67%, reduced poly(ADP-ribose)polymerase-1 expression and cleavage 2- to 4-fold, and elevated levels of p27 in the distal colon 3-fold. Studies in cancer cell cultures recapitulated actions of GT-094: antiproliferative activity and transient G₂-M phase cell cycle block were measured in Caco-2 cells; apoptotic activity was examined but not observed; anti-inflammatory activity was seen in the inhibition of up-regulation of iNOS and endogenous NO production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. In summary, antiproliferative, anti-inflammatory, and cytoprotective activity observed in vivo and in vitro support GT-094 as a lead compound for the design of NO chimeras for colorectal cancer chemoprevention. [Mol Cancer Ther 2007;6(8):2230–9]

Grant support: University of Illinois at Chicago Cancer Center, NIH grants CA-102590 and CA-80360, and VA Merit Review to R.E. Carroll.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/30/07; revised 5/12/07; accepted 6/15/07.

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