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: To examine whether tyropeptin-boronic acid derivatives inhibit the proteasome in tumors, we used HEK293PS cells that are continuously expressing a proteasome-sensitive fluorescent protein. AS-06 and AS-29 were administrated at doses that were fourfold higher than bortezomib, because AS-06 and AS-29 had fourfold lower acute toxicity on mice than bortezomib. Intravenous administration of AS-29 to mice bearing HEK293PS tumors significantly induced strong fluorescence in tumors at 24 h after administration (Fig. 4a). Compared with AS-06, AS-29 inhibited more potently the proteasome activity in tumors (Fig. 4b). Furthermore, we assessed the in vivo antitumor activity of tyropeptin-boronic acid derivatives using xenograft models of human multiple myeloma RPMI8226 cells ( Fig.4c). When administered i.v. twice weekly for 4 weeks, AS-06 moderately suppresses the growth of subcutaneous tumor of RPMI8226 xenograft, while AS-29 potently suppresses tumor growth. These results clearly show that tyropeptin-boronic acid derivatives inhibit the proteasome activity in tumors, and, in particular, AS-29 has potent antitumor activity.