Redox-sensitive transcription factors as prime targets for chemoprevention with anti-inflammatory and antioxidative phytochemicals

Oxidative stress has been implicated in various pathological conditions including cancer. However, the human body has an intrinsic ability to fight against oxidative stress. A wide array of phase 2 detoxifying or antioxidant enzymes constitutes a fundamental cellular defense system against oxidative and electrophilic insults. Transcriptional activation of genes encoding detoxifying and antioxidant enzymes by NF-E2 related factor 2 (Nrf2), a member of the cap'n'collar family of basic leucine zipper transcription factors, may protect cells and tissues from oxidative damage. Many chemopreventive and chemoprotective phytochemicals have been found to enhance cellular antioxidant capacity through activation of this particular transcription factor, thereby blocking initiation of carcinogenesis. A new horizon in chemoprevention research is the recent discovery of molecular links between inflammation and cancer. Components of the cell signaling pathways, especially those that converge on redox-sensitive transcription factors, including nuclear factor-kappaB (NF-kappa B) and activator protein 1 (AP-1) involved in mediating inflammatory response, have been implicated in carcinogenesis. A wide variety of chemopreventive and chemoprotective agents can alter or correct undesired cellular functions caused by abnormal proinflammatory signal transmission mediated by inappropriately activated NF-kappa B and AP-1. The modulation of cellular signaling by anti-inflammatory phytochemicals hence provides a rational and pragmatic strategy for molecular target-based chemoprevention.