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 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 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.
Department of Biology, University of Montevallo, Montevallo, AL, USA.
Heather N
HN
Tinsley
William E
WE
Grizzle
Ashraf
A
Abadi
Adam
A
Keeton
Bing
B
Zhu
Yaguang
Y
Xi
Gary A
GA
Piazza
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077022:Survivin
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; C107489:BIRC5 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D017382:Reactive Oxygen Species; D000077022:Survivin; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2