5-methoxyindole metabolites of L-tryptophan: control of COX-2 expression, inflammation and tumorigenesis

J Biomed Sci. 2014 Mar 3;21(1):17. doi: 10.1186/1423-0127-21-17.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

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

Substances

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