Antitumor effects of tyropeptin-boronic acid derivatives: New proteasome inhibitors.
Bottom Line: Here we report the antitumor effects of two new tyropeptin-boronic acid derivatives, AS-06 and AS-29.We show that these derivatives also suppress the degradation of the NF-κB inhibitor IκB-α and the nuclear translocation of NF-κB p65 in multiple myeloma cells, resulting in the inhibition of NF-κB activation.Our results indicate that tyropeptin-boronic acid derivatives could be lead therapeutic agents against human multiple myeloma.
Affiliation: Institute of Microbial Chemistry, Numazu, Japan.Show MeSH
Related in: MedlinePlus
Mentions: The transcription factor NF-κB is involved in cell growth and confers a significant survival potential in a variety of tumors. Inhibition of NF-κB activation by proteasome inhibitors, such as bortezomib, is considered to be the major mechanism of action of antitumor activity. To evaluate whether tyropeptin-boronic acid derivatives inhibit NF-κB activation, we examined the effect of these derivatives on the degradation of the NF-κB inhibitor IκB-α and the nuclear translocation of NF-κB p65 subunits in RPMI8226 cells (Fig. 2a). The stimulation by TNF-α drastically decreases IκB-α levels and promotes the nuclear translocation of NF-κB p65. AS-06 and AS-29 suppressed the decrease of IκB-α and increased IκB-α phosphorylation. Furthermore, AS-06 and AS-29 blocked the nuclear translocation of NF-κB p65 after TNF-α stimulation. To confirm the inhibition of NF-κB activation by the treatment of tyropeptin-boronic acid derivatives, we further examined whether AS-06 and AS-29 inhibit the DNA-binding activity of NF-κB p65 (Fig. 2b). The DNA-binding activity of NF-κB p65 was enhanced by TNF-α, but AS-06 and AS-29 repressed the DNA-binding activity of NF-κ B p65. Taken together, these results indicate that tyropeptin-boronic acid derivatives inhibit NF-κB activation by stabilizing IκB-α.