Natural products as targeted modulators of the nuclear factor-kappaB pathway.
The use of plant extracts to alleviate inflammatory diseases is centuries old and continues to this day. This review assesses the current understanding of the use of such plants and natural products isolated from them in terms of their action against the ubiquitous transcription factor, nuclear factor kappa B (NF-kappaB). As an activator of many pro-inflammatory cytokines and inflammatory processes the modulation of the NF-kappaB transduction pathway is a principal target to alleviate the symptoms of such diseases as arthritis, inflammatory bowel disease and asthma. Two pathways of NF-kappaB activation will first be summarised, leading to the IKK (IkappaB kinase) complex, that subsequently initiates phosphorylation of the NF-kappaB inhibitory protein (IKB). Natural products and some extracts are reviewed and assessed for their activity and potency as NF-kappaB inhibitors. A large number of compounds are currently known as NF-kappaB modulators and include the isoprenoids, most notably kaurene diterpenoids and members of the sesquiterpene lactones class, several phenolics including curcumin and flavonoids such as silybin. Additional data on cellular toxicity are also highlighted as an exclusion principle for pursuing such compounds in clinical development. In addition, where enough data exists some conclusions on structure-activity relationship are provided.
Bremner
Paul
P
Centre for Pharmacognosy and Phytotherapy, School of Pharmacy, London, UK. phyto@ams1ulsop.ac.uk
Heinrich
Michael
M
D000818:Animals; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D004224:Diterpenes / Q000737:chemistry; D005658:Fungi / Q000737:chemistry; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D010636:Phenols / Q000737:chemistry; D010766:Phosphorylation; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011161:Porifera / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry; D014315:Triterpenes / Q000737:chemistry; D014452:Ubiquitins / Q000378:metabolism
D001688:Biological Products; D004224:Diterpenes; D020672:I-kappa B Proteins; D016328:NF-kappa B; D010636:Phenols; D010936:Plant Extracts; D012717:Sesquiterpenes; D013729:Terpenes; D014315:Triterpenes; D014452:Ubiquitins; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human