期刊
CANCER SCIENCE
卷 105, 期 12, 页码 1609-1615出版社
WILEY
DOI: 10.1111/cas.12542
关键词
Antitumor effect; boronic acid; multiple myeloma; proteasome inhibitor; tyropeptin
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology in Japan [23510270]
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Grants-in-Aid for Scientific Research [23510270] Funding Source: KAKEN
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-B inhibitor IB- and the nuclear translocation of NF-B p65 in multiple myeloma cells, resulting in the inhibition of NF-B 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.
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