TM-233, a novel analog of 1'-acetoxychavicol acetate, induces cell death in myeloma cells by inhibiting both JAK/STAT and proteasome activities.
TM-233, a novel analog of 1'-acetoxychavicol acetate, induces cell death in myeloma cells by inhibiting both JAK/STAT and proteasome activities.
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DOI：
10.1111/cas.12616
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发表时间：
2015-04
期刊：
影响因子：
5.7
通讯作者：
Kizaki M
中科院分区：
文献类型：
--
作者：
Sagawa M;Tabayashi T;Kimura Y;Tomikawa T;Nemoto-Anan T;Watanabe R;Tokuhira M;Ri M;Hashimoto Y;Iida S;Kizaki M
虽然硼替佐米和免疫调节药物的引入改善了多发性骨髓瘤患者的预后，但这种疾病仍然无法治愈。为了寻找更有效和耐受性更好的骨髓瘤治疗药物，我们先前报道了1′-乙酰氧基胡椒酚乙酸酯（ACA），一种来自东南亚的天然调味品，通过抑制NF-κ B相关功能在体外和体内诱导骨髓瘤细胞凋亡。为了寻找更有效的NF-κB抑制剂，我们基于定量构效关系分析开发了几种ACA类似物。TM-233是这些ACA类似物之一，在各种骨髓瘤细胞系中以低于ACA的IC 50抑制细胞增殖并诱导细胞死亡。用TM-233处理抑制JAK 2和STAT 3的组成性激活，然后下调抗凋亡Mcl-1蛋白的表达，但不下调Bcl-2和Bcl-xL蛋白的表达。此外，TM-233可迅速降低NF-κB的核表达，并减少胞浆NF-κB的积聚。我们还检查了TM-233对我们最近建立的硼替佐米耐药骨髓瘤细胞KMS-11/BTZ和OPM-2/BTZ的影响。在KMS-11/BTZ和OPM-2/BTZ细胞中，TM-233而不是硼替佐米抑制细胞增殖并诱导细胞死亡。有趣的是，TM-233和硼替佐米的组合通过抑制NF-κB活性显著诱导这些硼替佐米耐药骨髓瘤细胞中的细胞死亡。这些结果表明，TM-233可以克服骨髓瘤细胞通过不同机制介导的硼替佐米耐药性，可能抑制JAK/STAT途径。结论：TM-233可能是一种比ACA更有效的NF-κB抑制剂，并能克服骨髓瘤细胞对硼替佐米的耐药性。
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.
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影响因子：
5.7
作者：
Nadiminty N;Tummala R;Liu C;Yang J;Lou W;Evans CP;Gao AC
通讯作者：
Gao AC
影响因子：
4.8
作者：
Heinemeyer, W;Fischer, M;Wolf, DH
通讯作者：
Wolf, DH
DOI：
10.1111/j.1349-7006.1996.tb00229.x
发表时间：
1996-04-01
期刊：
JAPANESE JOURNAL OF CANCER RESEARCH
影响因子：
--
作者：
Ohnishi, M;Tanaka, T;Koshimizu, K
通讯作者：
Koshimizu, K
影响因子：
20.3
作者：
Kumar, Shaji K.;Bensinger, William I.;Niesvizky, Ruben
通讯作者：
Niesvizky, Ruben
影响因子：
1.7
作者：
Misawa, Takashi;Aoyama, Hiroshi;Hashimoto, Yuichi
通讯作者：
Hashimoto, Yuichi