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Molecular Mechanism for Various Pharmacological Activities of NSAIDS
Pharmaceuticals 2010, 3(5), 1652-1667; doi:10.3390/ph3051652
Review

NSAIDs: Old Drugs Reveal New Anticancer Targets

1,2,* , 1, 2, 2, 1, 1, 3, 2 and 1,2
Received: 16 March 2010 / Revised: 5 May 2010 / Accepted: 10 May 2010 / Published: 25 May 2010
(This article belongs to the collection Non-Steroidal Anti-Inflammatory Drugs)
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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 on in silico modeling 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.
Keywords: NSAIDs; sulindac; cancer; colon; chemoprevention NSAIDs; sulindac; cancer; colon; chemoprevention
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Piazza, G.A.; Keeton, A.B.; Tinsley, H.N.; Whitt, J.D.; Gary, B.D.; Mathew, B.; Singh, R.; Grizzle, W.E.; Reynolds, R.C. NSAIDs: Old Drugs Reveal New Anticancer Targets. Pharmaceuticals 2010, 3, 1652-1667.

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