Open AccessTM ‐233, a novel analog of 1′‐acetoxychavicol acetate, induces cell death in myeloma cells by inhibiting both JAK / STAT and proteasome activities
Author(s) -
Sagawa Morihiko,
Tabayashi Takayuki,
Kimura Yuta,
Tomikawa Tatsuki,
NemotoAnan Tomoe,
Watanabe Reiko,
Tokuhira Michihide,
Ri Masaki,
Hashimoto Yuichi,
Iida Shinsuke,
Kizaki Masahiro
Publication year - 2015
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12616
Subject(s) - bortezomib , multiple myeloma , proteasome inhibitor , apoptosis , programmed cell death , pharmacology , cell growth , proteasome , in vivo , cancer research , chemistry , cell culture , medicine , biology , immunology , biochemistry , genetics , microbiology and biotechnology
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 IC 50 than ACA . Treatment with TM ‐233 inhibited constitutive activation of JAK 2 and STAT 3, 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.