NSAIDs Old Drugs Reveal New Anticancer Targets 英文参考文献.docVIP

Pharmaceuticals 2010, 3, 1652-1667; doi:10.3390/ph3051652 OPEN ACCESS pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review NSAIDs: Old Drugs Reveal New Anticancer Targets Gary A. Piazza 1,2,*, Adam B. Keeton 1 , Heather N. Tinsley 2, Jason D. Whitt 2, Bernard D. Gary 1, Bini Mathew 1, Raj Singh 3, William E. Grizzle 2 and Robert C. Reynolds 1,2 1 2 3 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 Vivo Biosciences Inc., 1601 12th Avenue South, Birmingham AL, 35205, USA * Author to whom correspondence should be addressed; E-Mail: piazza@; Tel. +1-205-581-2731; Fax: +1-205-581-2093. Received: 16 March 2010; in revised form: 5 May 2010 / Accepted: 10 May 2010 / Published: 25 May 2010 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