信号传导与转录激活因子3（STAT3）是存在于细胞浆与酪氨酸磷酸化信号通路偶联的双功能蛋白，STAT3高表达和活化与多发性骨髓瘤（MM）细胞异常增殖和凋亡以及耐药密切相关。课题组前期研究显示，青藤碱衍生物ZW016能够与MM细胞内STAT3结合并抑制其活化进而诱导MM细胞凋亡。鉴于此, 课题组提出如下假说：ZW016通过直接靶向STAT3而发挥抗MM效应。为证明此假说，课题组拟从以下方面进行研究：①临床水平验证MM患者骨髓瘤细胞内STAT3和磷酸化STAT3表达水平与其生存预后的相关性; ②在细胞水平检测ZW016抑制MM细胞内STAT3活化并诱导MM细胞增殖阻滞和凋亡的生物学效应以及ZW016与STAT3结合方式和位点; ③应用MM动物模型进一步检测ZW016抗MM生物学效应; ④探究ZW016与MM临床治疗常用药物的联合效应。本实验完成将为MM新型治疗药物研发提供理论基础和潜在靶标。

Signal transducer and activator of transcription 3 (STAT3) is a bi-functional protein which coupled with tyrosine phosphorylation signaling pathway. Overexpressed or highly activated STAT3 is closely associated with abnormal proliferation and apoptosis of multiple myeloma (MM) cells as well as chemoresistance to standard therapies. In our previous series of in vitro experiments, it was shown that ZW016, one of sinomenine derivatives from traditional Chinese medicine, could inhibit intracellular STAT3 activation and induces cell growth arrest and apoptosis in MM cells. Based on these results, we proposed that ZW016 could display potency in the treatment of myeloma through target modulating STAT3. To prove this hypothesis，this project intends to address the followings: ① Determine the relationship between expression levels of STAT3 and p-STAT3 and prognosis of MM patients. ② Assess biological effects of ZW016 in abrogating STAT3 activation, inhibiting cell proliferation and inducing apoptosis in MM cell lines. Furthermore, by using cell free analysis, validate the interaction of ZW016 and STAT3 as well as its precise binding cites. ③ Validate biological effects of ZW016 in distinct MM mice models. ④ Explore combined effects of ZW016 and first line therapeutic agents in MM. This study would provide insights for the development of anti-MM drugs and the theoretic instructions for drug targets identification.