Inhibiting NF-?B activation by small molecules as a therapeutic strategy.

ABSTRACT: Because nuclear factor-?B (NF-?B) is a ubiquitously expressed proinflammatory transcription factor that regulates the expression of over 500 genes involved in cellular transformation, survival, proliferation, invasion, angiogenesis, metastasis, and inflammation, the NF-?B signaling pathway has become a potential target for pharmacological intervention. A wide variety of agents can activate NF-?B through canonical and noncanonical pathways. Canonical pathway involves various steps including the phosphorylation, ubiquitination, and degradation of the inhibitor of NF-?B (I?B?), which leads to the nuclear translocation of the p50-p65 subunits of NF-?B followed by p65 phosphorylation, acetylation and methylation, DNA binding, and gene transcription. Thus, agents that can inhibit protein kinases, protein phosphatases, proteasomes, ubiquitination, acetylation, methylation, and DNA binding steps have been identified as NF-?B inhibitors. Because of the critical role of NF-?B in cancer and various chronic diseases, numerous inhibitors of NF-?B have been identified. In this review, however, we describe only small molecules that suppress NF-?B activation, and the mechanism by which they block this pathway.

SUBMITTER: Gupta SC 

PROVIDER: S-EPMC2955987 | biostudies-literature | 2010 Oct-Dec

REPOSITORIES: biostudies-literature