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.

多发性骨髓瘤是治愈难治性血液学恶性肿瘤，这将是新的治疗方法。基于干细胞生物学的最新进展，已被认为是针对骨髓瘤干/祖细胞（MSPC）开发新的治疗患者的疗法。在本项目中，我从天然化合物1'-乙酰氧基甲酸（ACA）（ACA）开发了新的NF-KB抑制剂TM233，其具有与ACA相比更有效的NF-KB抑制活性，并诱导骨髓瘤细胞的凋亡。另外，TM233诱导蛋白酶体抑制剂硼替佐米细胞的凋亡。因此，TM233预计将是未来的临床应用。金化合物Auranofin也通过抑制JAK/STAT和NF-KB信号通路诱导骨髓瘤细胞的凋亡。已经清除了CD138阴性血浆细胞分数在体外和体内存在的克隆发育MSPC。将需要进一步的研究来研究TM233，Auranofin和其他天然化合物对MSPC的影响。

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

形質細胞腫瘍と類縁疾患の治療:現状と将来展望

浆细胞肿瘤及相关疾病的治疗：现状与未来展望

• 发表时间: 2009
• 作者: 寺田蕗子、尾崎由枝、内藤悠平;鈴木裕也;柳川弘志;始平堂弘和、田原佳代子、山田健人;杜ぶん林;飯島史朗;松下麻衣子;服部豊;木崎昌弘
• 通讯作者: 木崎昌弘

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