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: Isao Momose, Hikaru Abe, Takumi Watanabe, Shun-ichi Ohba, Kanami Yamazaki, Shingo Dan, Takao Yamori, Tohru Masuda, Akio Nomoto
• Journal: Cancer science (Cancer Sci) Vol. 105 Issue 12 Pg. 1609-15 (Dec 2014) ISSN: 1349-7006 [Electronic] England
• PMID: 25251038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• AS-06 compound
• AS-29 compound
• Antineoplastic Agents
• Boronic Acids
• Dipeptides
• Proteasome Inhibitors

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Boronic Acids (pharmacology)
• Cell Line, Tumor
• Dipeptides (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Humans
• Mice
• Multiple Myeloma (drug therapy, pathology)
• Neoplasms, Experimental
• Proteasome Inhibitors (pharmacology)
• Ubiquitination (drug effects)
• Xenograft Model Antitumor Assays