Development of novel molecular-targeting therapy for multiple myeloma against its progenitor cells

开发针对多发性骨髓瘤祖细胞的新型分子靶向疗法

• 批准号: 21591219
• 负责人: KIZAKI Masahiro
• 金额: $ 2.91万
• 依托单位: Saitama Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21591219/
• 关键词: 多発性骨髄腫; 分子標的療法; 前駆細胞; アポトーシス; マウスモデル; NF-κB阻害剤

Multiple myeloma is a refractory hematological malignancy to cure, and it will be desired new therapeutic approaches. Based on the recent progress of the stem cell biology, it has been considered to develop the new therapy against the myeloma stem/progenitor cells(MSPC) to cure the patients. In the present project, I developed new NF-kB inhibitor, TM233, from natural compound 1'-acetoxychavicol acetate(ACA), which has more potent NF-kB inhibition activity than that of ACA and induces apoptosis of myeloma cells. In addition, TM233 induced apoptosis of proteasome inhibitor bortezomib-resistant myeloma cells ; therefore TM233 will expected to be future clinical application. Gold compound, auranofin, also induced apoptosis of myeloma cells via inhibition of JAK/STAT and NF-kB signaling pathways. It has been cleared that clonogenic MSPC is existed in CD138-negative plasma cell fraction in vitro and in vivo. Further studies will be needed to investigate the effect of TM233, auranofin and other natural compounds on MSPC.

多发性骨髓瘤是一种难以治愈的血液系统恶性肿瘤，需要新的治疗方法。基于干细胞生物学的最新进展，研究针对骨髓瘤干细胞/祖细胞（MSPC）的新疗法已被认为是治愈骨髓瘤患者的重要途径。在本项目中，我从天然化合物1′-acetoxychavicol acetate（ACA）中开发了新的NF-kB抑制剂TM233，该抑制剂具有比ACA更强的NF-kB抑制活性，可诱导骨髓瘤细胞凋亡。此外，TM233诱导蛋白酶体抑制剂硼替佐米耐药骨髓瘤细胞凋亡；因此，TM233有望在未来得到临床应用。金化合物金蛋白也通过抑制JAK/STAT和NF-kB信号通路诱导骨髓瘤细胞凋亡。体外和体内研究表明，克隆源性MSPC存在于cd138阴性浆细胞中。TM233、金糠蛋白和其他天然化合物对MSPC的影响有待进一步研究。

项目成果

多発性骨髄腫。血液疾患最新の治療2011-2013

多发性骨髓瘤。

• 发表时间: 2010
• 作者: 倉光球;浜口功;片山直之;木崎昌弘
• 通讯作者: 木崎昌弘

多発性骨髄腫の新たな治療展開

多发性骨髓瘤治疗新进展

• 发表时间: 2011
• 作者: Liu B;et al;木崎昌弘
• 通讯作者: 木崎昌弘

New therapeutic approach for multiple myeloma : Dvelopment of novel molecular targeting agents

多发性骨髓瘤的新治疗方法：新型分子靶向药物的开发

• 发表时间: 2011
• 作者: 松本剛史;他;Kizaki M
• 通讯作者: Kizaki M

The gold compound auranofin induces apoptosis of human multiple myeloma cells thrsough both down-regulation of STAT3 and inhibition of NF-κB activity.

金化合物金诺芬通过下调 STAT3 和抑制 NF-κB 活性来诱导人多发性骨髓瘤细胞凋亡。

• 期刊: Leuk Res(Epub 2010 Jun 12.)
• 作者: Nakaya A;et al
• 通讯作者: et al

形質細胞腫瘍の病態研究と治療開発の最近の進歩

浆细胞肿瘤的病理研究和治疗进展的最新进展

• 发表时间: 2009
• 作者: Yamazaki S;Minegishi N;et al.;木崎昌弘
• 通讯作者: 木崎昌弘