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，有望成为治疗多发性骨髓瘤的新途径。根据干细胞生物学的最新进展，目前已考虑开发针对骨髓瘤干细胞/祖细胞(MSPC)的新疗法来治愈患者。本课题以天然化合物1‘-乙酰氧基乙酸酯(ACA)为原料，开发了一种新的核因子-kB抑制剂TM233，它具有比ACA更强的核因子-kB抑制活性，并能诱导骨髓瘤细胞的凋亡。此外，TM233还可诱导蛋白酶体抑制剂Bortezomib耐药骨髓瘤细胞的凋亡，因此TM233有望在未来的临床应用中发挥作用。金化合物Auranofin还通过抑制JAK/STAT和NF-kB信号通路诱导骨髓瘤细胞凋亡。体内外研究表明，CD138阴性浆细胞中存在克隆性MSPC。还需要进一步研究TM233、金诺芬等天然化合物对MSPC的影响。

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.