Work

Molecular Design and Biological Activities of NF-κB Inhibitors

Year: 2002

Type: article

Abstract: NF-kappaB is a transcription factor that induces inflammatory cytokines and anti-apoptotic proteins. We designed a new NF-kappaB inhibitor that is based on the structe of the antibiotic epoxyquinomicin C. The designed compound, dehydroxymethyl-epoxyquinomicin (DHMEQ), inhibited the TNF-alpha-induced activation of NF-kappaB, and showed an anti-arthritic effect in mice. Recently, we looked into its mechanism of inhibition. DHMEQ inhibited the TNF-alpha-induced cellular DNA binding of nuclear NF-kappaB, but not the phosphorylation or degradation of I-kappaB. Moreover, DHMEQ inhibited the TNF-alpha-induced nuclear accumulation of p65, a component of NF-kappaB. On the other hand, DHMEQ did not inhibit the nuclear transport of Smad2 and the large T antigen. Also, it did not inhibit the TNF-alpha-induced activation of JNK, but synergistically induced apoptosis with TNF-alpha in human T cell leukemia Jurkat cells. Therefore, DHMEQ specifically inhibited the NF-kappaB-activating pathway in the TNF-alpha-treated cells. Taken together, our data show that DHMEQ is a unique inhibitor of NF-kappaB that acts at the level of the nuclear translocation. It may be useful as an anti-inflammatory and anticancer agent.

Source: Molecules and Cells

DOI: 10.1016/s1016-8478(23)15088-6

Authors: Kazuo Umezawa, Chanya Chaicharoenpong

Institution: Keio University

Language: English

Topic: NF-κB Signaling Pathways

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $2,500