I18 Cancer chemopreventive effects of natural products with anti-inflammatory and pro-resolving activities

Abstract

The implication of inflammation in the pathophysiology of human cancer is under intense investigation both at the research level and in clinical practice. Numerous studies have identified a series of critical molecules/changes in inflammatory signalling. Some of the key molecules involved in mediating proinflammatory signalling include NF-kB, STAT3, AP-1, HIF-1a, and p53. Nuclear factor E2-related factor-2 (Nrf2) plays a crucial role in regulating stress-responsive gene induction. This transcription factor is sequestered in the cytoplasm as an inactive complex with the inhibitory protein Keap1. Upon activation, Nrf2 binds to antioxidant responsive element (ARE) sites, leading to the coordinated up-regulation of target genes that encode many anti-inflammatory as well as antioxidant and other cytoprotective proteins. While chronic inflammation is detrimental, acute inflammation is a physiologic response to protect cells from microbial infection and other noxious stimuli. However, if timely resolution of inflammation fails, inflammation persists and can progress to a chronic state which has long been thought as a predisposing factor to many human disorders including cancer. Resolution of inflammation is an active process regulated co-ordinately by distinct anti-inflammatory and pro-resolving lipid mediators some of which are derived from n-3 polyunsaturated fatty acids. For efficacious prevention of inflammation-associated disorders, identification of natural products with the capability to stimulate/potentiate pro-resolving/anti-inflammatory processes as well as to suppress aberrant overactivation of proinflammatory ones merits further investigation. Our current research program concerns the identification of cancer chemopreventive and cytoprotective natural products that modulate key redox-sensitive transcription factors involved in proinflammatory or anti-inflammatory/pro-resolving signalling.