Oncotarget

Research Papers:

Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits

Takashi Yoshida _, Masaki Ri, Takashi Kanamori, Sho Aoki, Reham Ashour, Shiori Kinoshita, Tomoko Narita, Haruhito Totani, Ayako Masaki, Asahi Ito, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Shun Kitahata, Takuya Chiba, Satoshi Ichikawa and Shinsuke Iida

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Oncotarget. 2018; 9:9975-9991. https://doi.org/10.18632/oncotarget.24160

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Abstract

Takashi Yoshida1, Masaki Ri1, Takashi Kanamori1, Sho Aoki1, Reham Ashour1, Shiori Kinoshita1, Tomoko Narita1, Haruhito Totani1, Ayako Masaki1, Asahi Ito1, Shigeru Kusumoto1, Takashi Ishida1, Hirokazu Komatsu1, Shun Kitahata2, Takuya Chiba2, Satoshi Ichikawa2 and Shinsuke Iida1

1Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

2Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan

Correspondence to:

Masaki Ri, email: [email protected]

Keywords: multiple myeloma; syringolin analog; dual inhibitor; proteasome; bortezomib resistance

Received: July 12, 2017     Accepted: December 03, 2017     Published: January 11, 2018

ABSTRACT

Proteasome inhibitors (PI), mainly targeting the β5 subunit of the 20S proteasome, are widely used in the treatment of multiple myeloma (MM). However, PI resistance remains an unresolved problem in the therapy of relapsed and refractory MM. To develop a new PI that targets other proteasome subunits, we examined the anti-MM activity of a novel syringolin analog, syringolog-1, which inhibits the activity of both the β5 and β2 subunits. Syringolog-1 exhibited marked cytotoxicity against various MM cell lines and anti-tumor activity towards bortezomib (Btz)-resistant MM cells through the dual inhibition of chymotrypsin-like (β5 subunit) and trypsin-like (β2 subunit) activities. MM cells, including Btz-resistant cells, showed elevated CHOP and NOXA expression after syringolog-1 treatment, indicating the induction of excessive endoplasmic reticulum stress during syringolog-1 treatment. Similar activities of syringolog-1 were also observed in freshly prepared MM cells derived from patients. To clarify the anti-tumor mechanism of dual inhibition of both the β5 and β2 subunits of the proteasome, PSMB5 and PSMB7 were co-inhibited in MM cells. This resulted in increased apoptosis of MM cells accompanied by accumulation of ubiquitinated proteins compared to inhibition of either PSMB7 or PSMB5 alone, indicating an enhanced effect by double inhibition of β2 and β5 activities. In conclusion, this syringolin analog, a dual inhibitor of proteasome β2 and β5 activities, exhibited potent anti-tumor effects on MM cells and may be useful for overcoming Btz-resistance in the treatment of MM.


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