EDITORIALS COX-2 in Cancer—A Player That's Defining the Rules

Cyclooxygenase (COX) inhibitors are being developed as potential agents for the prevention and treatment of cancer after a century of widespread use for inflammation, fever, and pain. Beginning in the late 1970s, researchers noted elevated concentrations of prostaglandins in neoplastic lesions, which suggested a role for arachidonic acid metabolites in tumorigenesis. Multiple lines of evidence—in vitro, in vivo, observational, and clinical—now confirm that COX inhibitors reduce prostaglandin production and the risk of colorectal, skin, and other neoplasias (1). Owing to gastrointestinal safety concerns with traditional nonselective COX inhibitors, derivatives that selectively target COX-2 have been developed for applications in arthritis, analgesia, and the treatment of neoplasia. COX-2 selective inhibitors serve as a paradigm of molecularly targeted, cytostatic, antineoplastic agents (2). COX-2 is consistently overexpressed in a large percentage and variety of human and rodent tumors (3). Pathogenic relevance to in vivo carcinogenesis was demonstrated via genetic manipulations that either eliminated (4) or induced (5) COX-2 expression, resulting in substantial tumor reduction or stimulation, respectively. Food and Drug Administration (FDA)-approved selective COX-2 inhibitors, such as celecoxib (Celebrex™; Pharmacia, Peapack, NJ) or rofecoxib (Vioxx™; Merck, Whitehouse Station, NJ), effectively modulate inflammation and pain (6). Moreover, celecoxib has recently been shown to reduce the colorectal adenoma burden in high-risk patients (7). Cancer researchers, however, have reported COX-independent effects that are dose dependent, suggesting that mechanisms other than COX suppression alone may account for the observed efficacy of these agents. At the cellular level, COX inhibitors have been shown to inhibit proliferation, induce apoptosis, inhibit angiogenesis, reduce carcinogen activation, and stimulate the immune system (3,8). Although reductions in prostanoid concentrations may underlie these observed activities, non-COX targets and mechanisms may be involved as well. For example, nonselective COX inhibitors have been shown to modulate levels of cGMP (guanosine 3,5-cyclic monophosphate), NF-B (nuclear factor-B) activation, Bcl expression, and the binding of peroxisome pro