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: Kenneth K Wu, Huei-Hsuan Cheng, Tzu-Ching Chang
• Journal: Journal of biomedical science (J Biomed Sci) Vol. 21 Pg. 17 (Mar 03 2014) ISSN: 1423-0127 [Electronic] England
• PMID: 24589238 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Indoles
• Serotonin
• Tryptophan
• 5-methoxyindole
• Cyclooxygenase 2
• PTGS2 protein, human
• Melatonin

Topics

• Carcinogenesis (genetics)
• Cyclooxygenase 2 (biosynthesis, genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Indoles (metabolism)
• Inflammation (genetics)
• Melatonin (genetics, metabolism)
• Neoplasm Metastasis
• Neoplasms (genetics)
• Serotonin (metabolism)
• Tryptophan (metabolism)