NSAIDs: Old Drugs Reveal New Anticancer Targets

Pharmaceuticals

Gary A. Piazza²  Adam B. Keeton²  Heather N. Tinsley¹  Jason D. Whitt¹  Bernard D. Gary²  Bini Mathew²  Raj Singh³  William E. Grizzle¹ 

[1] The University of Alabama at Birmingham, 703 19^th Street South, Birmingham AL, 35294, USA;Southern Research Institute, 2000 9^th Avenue South, Birmingham AL, 35205, USA;Vivo Biosciences Inc., 1601 12^th Avenue South, Birmingham AL, 35205, USA

关键词: NSAIDs;    sulindac;    cancer;    colon;    chemoprevention;   

DOI  :  10.3390/ph3051652

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2010 by the authors; licensee MDPI, Basel, Switzerland.