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，我们鉴定出丰加霉素（一种腺苷类似物）是从放线菌菌株的培养液中分离出来的 XBP1 抑制剂。 Toyocamycin 以及其他腺苷类似物可抑制 XBP1 激活并诱导 ER 应激肿瘤细胞凋亡。此外，丰加霉素抑制MM细胞中XBP1的组成型激活，与硼替佐米表现出协同细胞毒作用，并引发MM细胞系以及原代MM细胞的剂量依赖性凋亡。 Toyocamycin 显示出纳摩尔水平的生物活性，并在 MM 异种移植模型中介导与硼替佐米类似的生长抑制作用。这些结果为针对免疫调节药物和硼替佐米难治的多发性骨髓瘤患者单独或与硼替佐米联合使用丰加霉素或其他腺苷类似物启动临床试验提供了依据。此外，丰加霉素可能是进一步开发 IRE1-XBP-1 通路更特异性抑制剂的先导化合物。