title: 5-methoxyindole metabolites of L-tryptophan: control of COX-2 expression, inflammation and tumorigenesis.
abstract: Cyclooxygenase-2(COX-2) overexpression promotes inflammation and tumorigenesis. COX-2 expression in response to diverse stimuli is tightly controlled to avoid persistent overexpression. 5-methoxyindole metabolites of L-tryptophan represent a new class of compounds that control COX-2 expression at the transcriptional level. Two of the metabolites, the newly discovered 5-methoxytryptophan (5-MTP, also known as cytoguardin) and N-acetyl 5-methoxytryptamine (melatonin) are the focus of this review. 5-MTP is produced by mesenchymal cells such as fibroblasts via 5-hydroxytryptophan (5-HTP). It inhibits COX-2 transcriptional activation induced by diverse proinflammatory and mitogenic factors. Cancer cells are deficient in cytoguardin production which contributes to COX-2 overexpression. Fibroblast-generated 5-MTP is capable of restoring the control of COX-2 overexpression in cancer cells. 5-MTP blocks cancer cell migration and invasion in vitro and inhibits tumor growth and cancer metastasis in a xenograft model. Melatonin possesses similar COX-2 suppressing and anti-cancer properties albeit at supra-pharmacological concentrations. By contrast, 5-hydroxyindole metabolites of L-tryptophan such as 5-hydroxytryptamine (serotonin), 5-hydroxytryptophol and other serotonin catabolites do not control COX-2 expression. 5-hydroxytryptophan inhibits COX-2 expression through conversion to 5-MTP. The physiological relevance of 5-MTP as an endogenous regulator of inflammation and cancer metastasis remains to be investigated. On the other hand, 5-methoxyindole metabolites of tryptophan are valuable lead compounds for development of new anti-inflammatory drugs and cancer chemoprevention.
authors.affiliation: Metabolomic Medicine Research Center, and Graduate Institutes of Basic and Clinical Medicine Science, China Medical University and Hospital, Taichung, Taiwan. kkwugo@gmail.com.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
authors.forename: Huei-Hsuan
authors.initials: HH
authors.lastname: Cheng
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Chang
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics; D008550:Melatonin / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D007211:Indoles; D012701:Serotonin; D014364:Tryptophan; C487413:5-methoxyindole; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D008550:Melatonin