Identification of angular naphthopyrones from the Philippine echinoderm Comanthus species as inhibitors of the NF-κB signaling pathway

The redox-sensitive nuclear factor kappa-B (NF-kappa B) signaling pathway is an important cellular pathway often misregulated in various cancer cells. Therefore, blockade of NF-kappa B signaling in cancer cells presents a promising strategy and enormous effort has been invested to identify potent and specific inhibitors. The aim of this study was the identification of new compounds derived from marine organisms that act as NF-kappa B inhibitors and to identify their mechanism of action. In the present work a bioassay-guided investigation of a Philippine specimen of the marine echinoderm Comanthus sp. yielded ten compounds evenly divided into anthraquinones and naphthopyrones. From these compounds only two naphthopyrones, comaparvin and 6-methoxycomaparvin exhibited noteworthy inhibitory activity against tumor necrosis factor-alpha (TNF-alpha) induced NF-kappa B activation in rat hepatoma cells and human breast cancer cells. Comaparvin at concentrations between 50 mu M and 100 mu M reduces chymotrypsin-like proteasomal activity, blocks nuclear translocation of NF-kappa B and effectively inhibits TNF-alpha induced I kappa B phosphorylation suggesting a role of this compound in targeting I kappa B kinase (IKK). Furthermore, comaparvin sensitized cancer cells to apoptotic effects mediated by the pro-inflammatory cytolcine TNF-alpha. These results correlate with downregulation of TNF-alpha induced expression of protective NF-kappa B target genes like MnSOD, XIAP or A20. In conclusion we identified the naphthopyrone comaparvin isolated from the marine echinoderm Comanthus sp. as a new inhibitor of the NF-kappa B signaling pathway acting by targeting both proteasome function and I kappa B phosphorylation likely by direct inhibitory effect on IKK beta activity. (C) 2011 Elsevier B.V. All rights reserved.