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Yoshida T, Ri M, Kanamori T, et al. Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits. Oncotarget. 2018;9(11):9975-9991doi: 10.18632/oncotarget.24160.
Yoshida, T., Ri, M., Kanamori, T., Aoki, S., Ashour, R., Kinoshita, S., Narita, T., Totani, H., Masaki, A., Ito, A., Kusumoto, S., Ishida, T., Komatsu, H., Kitahata, S., Chiba, T., Ichikawa, S., & Iida, S. (2018). Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits. Oncotarget, 9(11), 9975-9991. https://doi.org/10.18632/oncotarget.24160
Yoshida, Takashi, et al. "Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits." Oncotarget vol. 9,11 (2018): 9975-9991. doi: https://doi.org/10.18632/oncotarget.24160
Yoshida T, Ri M, Kanamori T, Aoki S, Ashour R, Kinoshita S, Narita T, Totani H, Masaki A, Ito A, Kusumoto S, Ishida T, Komatsu H, Kitahata S, Chiba T, Ichikawa S, Iida S. Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits. Oncotarget. 2018 Jan 11;9(11):9975-9991. doi: 10.18632/oncotarget.24160. eCollection 2018 Feb 09. PMID: 29515784; PMCID: PMC5839415.
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Oncotarget. 2018 Jan 11;9(11):9975-9991. doi: 10.18632/oncotarget.24160. eCollection 2018 Feb 09.

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

Oncotarget

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, Shinsuke Iida

Affiliations

  1. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  2. Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan.

PMID: 29515784 PMCID: PMC5839415 DOI: 10.18632/oncotarget.24160

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,

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

Conflict of interest statement

CONFLICTS OF INTEREST MR received research funding from Celgene Co., Ltd. TI received research funding from Kyowa Hakko Kirin Co., Ltd., Bayer Pharma AG, and J-Pharma Co., Ltd. TI also received Honora

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