COX-Independent Mechanisms of Cancer Chemoprevention by Anti-Inflammatory Drugs

Abstract

Epidemiological and clinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase (COX)-2 selective inhibitors, reduce the risk of developing cancer. Experimental studies in human cancer cell lines and rodent models of carcinogenesis support these observations by providing strong evidence for the antineoplastic properties of NSAIDs. The involvement of COX-2 in tumorigenesis and its overexpression in various cancer tissues suggest that inhibition of COX-2 is responsible for the chemopreventive efficacy of these agents. However, the precise mechanisms by which NSAIDs exert their antiproliferative effects are still a matter of debate. Numerous other studies have shown that NSAIDs can act through COX-independent mechanisms. This review provides a detailed description of the major COX-independent molecular targets of NSAIDs and discusses how these targets may be involved in their anticancer effects. Toxicities resulting from COX inhibition and the suppression of prostaglandin synthesis preclude the long-term use of NSAIDs for cancer chemoprevention. Furthermore, chemopreventive efficacy is incomplete and treatment often leads to the development of resistance. Identification of alternative NSAID targets and elucidation of the biochemical processes by which they inhibit tumor growth could lead to the development of safer and more efficacious drugs for cancer chemoprevention.

Keywords: NSAIDs; cancer; chemoprevention; colon; sulindac; targets.

Figure 1

Chemical structures of common NSAIDs and selective COX-2 inhibitors.

Figure 2

The arachidonic acid cascade and cancer development. COX enzymes catalyze the conversion of arachidonic acid into prostaglandin H₂, the precursor for all prostaglandins (PGs) and thromboxane A₂ (TXA₂). PGH₂ is further converted into PGD₂, PGE₂, PGI₂, PGF₂α, and TXA₂ by specific synthases. These molecules mediate inflammation and are also involved in gastrointestinal epithelium homeostasis, platelet activation, and kidney function. Prostaglandins can also promote cell proliferation, angiogenesis, metastasis, and inhibit apoptosis leading to tumor growth.

Figure 3

Metabolism of sulindac. Prodrug sulindac undergoes reversible reduction into the active sulfide form through the action of liver enzymes and colonic bacteria. Sulindac sulfide is a non-selective COX inhibitor and is responsible for the anti-inflammatory properties of sulindac. The sulfone metabolite is generated by irreversible oxidation of the sulfoxide in the liver, and does not have anti-inflammatory activity. Both sulindac sulfide and sulindac sulfone have antineoplastic activity in vitro and in vivo.

Figure 4

Mechanistic model for the antineoplastic properties of sulindac. Inhibition of PDE5 and potentially other PDE isozymes by sulindac metabolites leads to an elevation of intracellular cGMP levels activating protein kinase G. PKG activation can lead to the induction of apoptosis, and inhibition of proliferation and angiogenesis through activation of JNK1 and downregulation of β-catenin-mediated transcription.

Figure 5

Chemical structures of non-COX-inhibitory derivatives of sulindac and celecoxib.