Anticancer agent CHS 828 suppresses nuclear factor‐κB activity in cancer cells through downregulation of IKK activity

CHS 828, a pyridyl cyanoguanidine, has been shown to exert a significant antitumor effect in preclinical tests in vitro and in vivo, and CHS 828 is in phase I/II clinical trials. We have investigated the effect of CHS 828 on the nuclear factor‐κB (NF‐κB) because of its well‐known role in the control of cell division and apoptosis. CHS 828 is able to inhibit the lipopolysaccharide (LPS)‐induced nuclear localization as well as the transcriptional activity of NF‐κB in human THP‐1 leukemia cells. Moreover, CHS 828 has also been shown to inhibit the LPS‐induced degradation of the IκBα and IκBβ in THP‐1 cells, leading us to identify the IκB kinase complex as a molecular target of CHS 828. The IKK activity is inhibited by CHS 828 with an IC50 of 8 nM. The inhibition of the IKK activity by different CHS 828 analogues correlates well with the inhibition of NYH small cell lung cancer cell proliferation in vitro and in vivo. Moreover, the inhibition of NF‐κB transcriptional activity in different cancer cell lines by CHS 828 correlates to some extent with the reduction by CHS 828 of the size of the corresponding xenografts. Activation of NF‐κB has been shown to induce expression of antiapoptotic proteins, and cancer cells have been shown to have high levels of constitutively active NF‐κB. Therefore, we hypothesize that the anticancer activity of CHS 828 is due to inhibition of the IKK activity by which the antiapoptotic protection of NF‐κB is removed, leading to the promotion of apoptosis. © 2004 Wiley‐Liss, Inc.