New NSAID Targets and Derivatives for Colorectal Cancer Chemoprevention
Clinical and preclinical studies provide strong evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent numerous types of cancers, especially colorectal cancer. Unfortunately, the depletion of physiologically important prostaglandins due t
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Abstract
Clinical and preclinical studies provide strong evidence that nonsteroidal antiinflammatory drugs (NSAIDs) can prevent numerous types of cancers, especially colorectal cancer. Unfortunately, the depletion of physiologically important prostaglandins due to cyclooxygenase (COX) inhibition results in potentially fatal toxicities that preclude the long-term use of NSAIDs for cancer chemoprevention. While studies have shown an involvement of COX-2 in colorectal tumorigenesis, other studies suggest that a COX-independent target may be at least partially responsible for the antineoplastic activity of NSAIDs. For example, certain NSAID derivatives have been identified that do not inhibit COX-2 but have demonstrated efficacy to suppress carcinogenesis with potential for reduced toxicity. A number of alternative targets have also been
H. N. Tinsley Department of Biology, Chemistry, and Mathematics, University of Montevallo, Montevallo, AL, USA W. E. Grizzle Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA A. Abadi Faculty of Pharmacy and Biotechnology, German University of Cairo, Cairo, Egypt A. Keeton B. Zhu Y. Xi G. A. Piazza (&) Drug Discovery Research Center Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Suite 3029, Mobile, AL 36604, USA e-mail: [email protected]
A. T. Chan and E. Detering (eds.), Prospects for Chemoprevention of Colorectal Neoplasia, Recent Results in Cancer Research 191, DOI: 10.1007/978-3-642-30331-9_6, Ó Springer-Verlag Berlin Heidelberg 2013
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reported to account for the tumor cell growth inhibitory activity of NSAIDs, including the inhibition of cyclic guanosine monophosphate phosphodiesterases (cGMP PDEs), generation of reactive oxygen species (ROS), the suppression of the apoptosis inhibitor protein, survivin, and others. Here, we review several promising mechanisms that are being targeted to develop safer and more efficacious NSAID derivatives for colon cancer chemoprevention.
Contents 1 Introduction.......................................................................................................................... 106 2 Targeting COX-2................................................................................................................. 109 3 COX-Independent Targets................................................................................................... 110 3.1 Inhibition of cGMP PDEs.......................................................................................... 110 3.2 Generation of Reactive Oxygen Species ................................................................... 112 3.3 Downregulation of Survivin....................................................................................... 113 3.4 Other COX-Independent Targets ............................................................................... 113 4 Conclusions.................................................................................................................
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