Study of the agent targetting for ER stress-induced XBP1 activity in refractory lymphoid malignancies.

难治性淋巴恶性肿瘤中 ER 应激诱导的 XBP1 活性靶向药物的研究。

• 批准号: 23791085
• 负责人: RI MASAKI
• 金额: $ 2.33万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23791085/
• 关键词: 骨髄腫; XBP1; T細胞性リンパ腫

In this study, we identified toyocamycin, an adenosine analog, as an XBP1 inhibitor isolated from culture broth of an Actinomycete strain. Toyocamycin as well as other adenosine analogs suppressed XBP1 activation and induced apoptosis in ER-stressed tumor cells. In addition, toyocamycin inhibited the constitutive activation of XBP1 in MM cells, showed synergistic cytotoxic effects with bortezomib, and triggered dose-dependent apoptosis of MM cell lines as well as primary MM cells. Toyocamycin showed biological activities at the nanomolar level and mediated a growth inhibitory effect in an MM xenograft model similar to bortezomib. These results provide a rationale for initiating clinical trials using toyocamycin or other adenosine analogs, alone or in combination with bortezomib, for patients with MM refractory to immunomodulatory drugs and bortezomib. Also, toyocamycin could be a lead compound to further develop more specific inhibitors of the IRE1-XBP-1 pathway.

在这项研究中，我们从一株放线菌的发酵液中分离出一种腺苷类似物--托伊卡霉素，作为XBP1抑制剂。丰田霉素和其他腺苷类似物抑制了XBP1的激活，并诱导了ER应激瘤细胞的凋亡。此外，托卡霉素还能抑制MM细胞XBP1的组成性激活，与Bortezomib有协同的细胞毒作用，并可诱导MM细胞系和原代MM细胞发生剂量依赖性的凋亡。丰霉素在纳米分子水平上显示出生物活性，并在类似于Bortezomib的MM异种移植模型中介导了生长抑制效应。这些结果为单独或与波特佐米联合使用托卡霉素或其他腺苷类似物对免疫调节药物和波特佐米无效的多发性骨髓瘤患者启动临床试验提供了理论依据。此外，托卡霉素可能是进一步开发更具特异性的IRE1-XBP-1途径抑制剂的先导化合物。

项目成果

Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing.

• DOI: 10.1038/bcj.2012.26
• 发表时间: 2012-07
• 期刊: BLOOD CANCER JOURNAL
• 影响因子: 12.8
• 作者: Ri, M.;Tashiro, E.;Oikawa, D.;Shinjo, S.;Tokuda, M.;Yokouchi, Y.;Narita, T.;Masaki, A.;Ito, A.;Ding, J.;Kusumoto, S.;Ishida, T.;Komatsu, H.;Shiotsu, Y.;Ueda, R.;Iwawaki, T.;Imoto, M.;Iida, S.
• 通讯作者: Iida, S.