Inflammation and cancer prevention.

Carcinogenesis is a multiyear, multistep, multipath disease of progressive genetic and associated tissue damage. Chemoprevention—defined as the use of drugs or other agents to inhibit, delay or reverse this process—is recognized as a very promising and important area in clinical cancer research [1, 2] and has proved to be an effective strategy for risk reduction of breast, prostate and colorectal cancer (CRC) [3–5]. Several epidemiologic [6] and experimental [7] data implicate inflammation as an important factor in neoplastic progression via production of oxygen and nitrogen radical oxidants, production of growth-promoting cytokines, tumor suppressor inhibition and stimulation of signal transduction pathways. Nuclear factor-jB (NF-jB), a protein induced during inflammation that serves as a transcription factor regulating genes for inflammatory and tumor-promoting proteins could prove to be a key molecular target for chemoprevention [8]. Evidence suggests that NF-jB has a role in carcinogenesis and cancer progression. Inflammatory agents, carcinogens, tumor promoters and the tumor microenvironment activate NF-jB. Both NF-jB and NF-jB-regulated proteins have been linked to cellular transformation, proliferation, apoptosis suppression, invasion, angiogenesis and metastasis. Moreover, constitutively activated NF-jB occurs in many tumors [8]. Agents modulating molecular targets of inflammation such as cyclooxygenase (COX) [7], inducible nitric oxide synthase (NOS) [9] and lipoxygenase (LOX) [10], have shown promising chemopreventive activity. In particular, COX inhibitors—including aspirin, traditional non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 selective inhibitors—have shown chemopreventive efficacy in epidemiologic analyses as well as in clinical studies and are being evaluated in numerous cancer targets where COX-2 overexpression or inflammation is observed. Many natural antioxidants (e.g. green tea polyphenols, lycopene, resveratrol, curcumin and sulforaphane) have broad-spectrum anti-inflammatory and free radical trapping activities. These agents have shown chemopreventive activity in animal models [11], are associated with lower cancer risk in human studies [12] and seem to be good candidates for development. The characterization of molecular targets of antioxidants has been difficult because of the pleiotropic activities of these agents. Attention is now being directed to Nrf2, a transcription factor that activates genes whose products are involved in deactivating electrophilic toxic compounds. Nrf2 can be activated by both natural and synthetic antioxidants (e.g. oltipraz, CDDO and its derivatives) [13]. Several cancers have been linked to inflammatory origin, as shown in Table 1. Evidence now suggests that inflammation [15] may be associated with increased risk of the four ‘big killers’, i.e. prostate [16], colon [17], breast [18] and lung [19] cancer. In the present article, we review epidemiological and clinical studies showing an association between use of antiinflammatory agents and risk reduction of these neoplasms.