title: NSAIDs: Old Drugs Reveal New Anticancer Targets.
abstract: There is compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 selective inhibitors have antineoplastic activity, but toxicity from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins limits their use for cancer chemoprevention. Previous studies as reviewed here suggest that the mechanism for their anticancer properties does not require COX inhibition, but instead involves an off-target effect. In support of this possibility, recent molecular modeling studies have shown that the NSAID sulindac can be chemically modified to selectively design out its COX-1 and COX-2 inhibitory activity. Unexpectedly, certain derivatives that were synthesized based onin silicomodeling displayed increased potency to inhibit tumor cell growth. Other experiments have shown that sulindac can inhibit phosphodiesterase to increase intracellular cyclic GMP levels and that this activity is closely associated with its ability to selectively induce apoptosis of tumor cells. Together, these studies suggest that COX-independent mechanisms can be targeted to develop safer and more efficacious drugs for cancer chemoprevention.
authors.affiliation: Southern Research Institute, 2000 9th Avenue South, Birmingham AL, 35205, USA. piazza@southernresearch.org.|The University of Alabama at Birmingham, 703 19th Street South, Birmingham AL, 35294, USA. piazza@southernresearch.org.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
authors.affiliation: Southern Research Institute, 2000 9th Avenue South, Birmingham AL, 35205, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Keeton
authors.affiliation: The University of Alabama at Birmingham, 703 19th Street South, Birmingham AL, 35294, USA.
authors.forename: Heather N
authors.initials: HN
authors.lastname: Tinsley
authors.affiliation: The University of Alabama at Birmingham, 703 19th Street South, Birmingham AL, 35294, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Whitt
authors.affiliation: Southern Research Institute, 2000 9th Avenue South, Birmingham AL, 35205, USA.
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Gary
authors.affiliation: Southern Research Institute, 2000 9th Avenue South, Birmingham AL, 35205, USA.
authors.forename: Bini
authors.initials: B
authors.lastname: Mathew
authors.affiliation: Vivo Biosciences Inc., 1601 12th Avenue South, Birmingham AL, 35205, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Singh
authors.affiliation: The University of Alabama at Birmingham, 703 19th Street South, Birmingham AL, 35294, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.affiliation: Southern Research Institute, 2000 9th Avenue South, Birmingham AL, 35205, USA.|The University of Alabama at Birmingham, 703 19th Street South, Birmingham AL, 35294, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reynolds
keywords: NSAIDs; cancer; chemoprevention; colon; sulindac