title: Antitumor effects of tyropeptin-boronic acid derivatives: New proteasome inhibitors.
abstract: The proteasome degrades numerous regulatory proteins that are critical for tumor growth. Thus, proteasome inhibitors are promising antitumor agents. New proteasome inhibitors, such as tyropeptins and tyropeptin-boronic acid derivatives, have a potent inhibitory activity. Here we report the antitumor effects of two new tyropeptin-boronic acid derivatives, AS-06 and AS-29. AS-06 and AS-29 significantly suppress the degradation of the proteasome-sensitive fluorescent proteins in HEK293PS cells, and induce the accumulation of ubiquitinated proteins in human multiple myeloma cells. 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. Furthermore, we demonstrate that AS-06 and AS-29 induce apoptosis through the caspase-8 and caspase-9 cascades. In a xenograft mouse model, i.v. administration of tyropeptin-boronic acid derivatives inhibits proteasome in tumors and clearly suppresses tumor growth in mice bearing human multiple myeloma. Our results indicate that tyropeptin-boronic acid derivatives could be lead therapeutic agents against human multiple myeloma.
authors.affiliation: Institute of Microbial Chemistry, Numazu, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Momose
authors.forename: Hikaru
authors.initials: H
authors.lastname: Abe
authors.forename: Takumi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Shun-ichi
authors.initials: S
authors.lastname: Ohba
authors.forename: Kanami
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Tohru
authors.initials: T
authors.lastname: Masuda
authors.forename: Akio
authors.initials: A
authors.lastname: Nomoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009374:Neoplasms, Experimental; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595265:AS-06 compound; C000595266:AS-29 compound; D000970:Antineoplastic Agents; D001897:Boronic Acids; D004151:Dipeptides; D061988:Proteasome Inhibitors
keywords: Antitumor effect; boronic acid; multiple myeloma; proteasome inhibitor; tyropeptin