TM‐233, a novel analog of 1′‐acetoxychavicol acetate, induces cell death in myeloma cells by inhibiting both JAK/STAT and proteasome activities

Cancer Science

Morihiko Sagawa³  Takayuki Tabayashi³  Yuta Kimura³  Tatsuki Tomikawa³  Tomoe Nemoto-Anan³  Reiko Watanabe³  Michihide Tokuhira³  Masaki Ri¹  Yuichi Hashimoto²  Shinsuke Iida¹ 

[1] Department of Medical Oncology and Immunology, Nagoya City University, Nagoya, Japan;Institute of Molecular and Cellular Biosciences, Tokyo University, Tokyo, Japan;Department of Hematology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

关键词: 1′‐acetoxychavicol acetate;    apoptosis;    bortezomib;    multiple myeloma;    NF‐κB;   

DOI  :  10.1111/cas.12616

来源: Wiley

【 摘 要 】

Abstract

Although the introduction of bortezomib and immunomodulatory drugs has led to improved outcomes in patients with multiple myeloma, the disease remains incurable. In an effort to identify more potent and well-tolerated agents for myeloma, we have previously reported that 1′-acetoxychavicol acetate (ACA), a natural condiment from South-East Asia, induces apoptotic cell death of myeloma cells in vitro and in vivo through inhibition of NF-κB-related functions. Searching for more potent NF-κB inhibitors, we developed several ACA analogs based on quantitative structure–activity relationship analysis. TM-233, one of these ACA analogs, inhibited cellular proliferation and induced cell death in various myeloma cell lines with a lower IC₅₀ than ACA. Treatment with TM-233 inhibited constitutive activation of JAK2 and STAT3, and then downregulated the expression of anti-apoptotic Mcl-1 protein, but not Bcl-2 and Bcl-xL proteins. In addition, TM-233 rapidly decreased the nuclear expression of NF-κB and also decreased the accumulation of cytosolic NF-κB. We also examined the effects of TM-233 on bortezomib-resistant myeloma cells that we recently established, KMS-11/BTZ and OPM-2/BTZ. TM-233, but not bortezomib, inhibited cellular proliferation and induced cell death in KMS-11/BTZ and OPM-2/BTZ cells. Interestingly, the combination of TM-233 and bortezomib significantly induced cell death in these bortezomib-resistant myeloma cells through inhibition of NF-κB activity. These results indicate that TM-233 could overcome bortezomib resistance in myeloma cells mediated through different mechanisms, possibly inhibiting the JAK/STAT pathway. In conclusion, TM-233 might be a more potent NF-κB inhibitor than ACA, and could overcome bortezomib resistance in myeloma cells.

【 授权许可】

CC BY-NC-ND   
© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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