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

多发性骨髓瘤是一种难治性血液系统恶性肿瘤，需要新的治疗方法。基于干细胞生物学的最新进展，开发针对骨髓瘤干/祖细胞（MSPC）的新疗法已被考虑。在本项目中，我从天然化合物1 '-乙酰氧基胡椒酚乙酸酯（ACA）开发了新的NF-κ B抑制剂TM 233，其具有比ACA更强的NF-κ B抑制活性，并诱导骨髓瘤细胞凋亡。此外，TM 233还能诱导蛋白酶体抑制剂硼替唑米耐药骨髓瘤细胞凋亡，因此TM 233有望成为未来的临床应用。金化合物金诺芬也通过抑制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，CD 138阴性浆细胞组分中存在克隆性MSPC。TM 233、金诺芬和其他天然化合物对MSPC的影响还需进一步研究。

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.