黄芩素诱导白血病细胞凋亡和克服耐药的分子机制探讨

Leukemia treatment strategy is still facing many problems. For instance, the prognosis of acute megakaryoblastic leukemia is dismal with a median survival of approximate 40 weeks and the resistance to tyrosine kinase inhibitors is a major challenge for targeted therapy of chronic myeloid leukemia. Novel therapy for these diseases is urgently needed. Previously, we treated acute and chronic myeloid leukemia patients with Huang-lian-jie-du-tang, a traditional Chinese medical prescription, and observed fairly good clinic response. Preliminary study also showed that baicalein, one of major active ingredients in the decoction, potently inhibited proliferation of multiple leukemic cell lines including 6133/MPL W515L, CMK, K562, HEL, HL-60, U937, Jurkat, Raji. Thus, we propose to explore the moleculars involved in anti-leukemia activity of baicalein in this proposal. We will explore the molecular mechanism by which baicalein induces apoptosis, prevents cell cycle progress, suppresses inflammation, regulates signal transduction and gene transcription. We will further probe the potential mechanism by which baicalein may overcome the resistance to tyrosine kinase inhibitors in chronic myeloid leukemia. At primary cell level, we will verify anti-leukemia efficacy of baicalein in cells from chronic myeloid leukemia patients. By using 6133/MPL W515L and BCR-ABL-transduced primary bone marrow cells, we can establish two mouse models for acute megakaryoblastic leukemia and chronic myeloid leukemia, respectively. At mouse individual level, we will ultimately confirm that baicalein can effectively suppress leukemia development in these two models and interfere leukemic stem/progenitor cell self-renewal function. The implementation of this project will provide strong scientific evidence to support the application of baicalein in leukemia treatment. It is also a useful exploration in traditional Chinese medicine to develop novel strategy for leukemia patient treatment.

急性巨核细胞白血病缺乏有效疗法，而慢性粒细胞白血病的靶向治疗面临耐药性的难题，亟需开发新疗法。黄连解毒汤辅助治疗急慢性粒细胞白血病具有良好的临床反应；前期实验研究证实组方中的有效成分黄芩素能抑制多种白血病细胞系增殖。本项目计划深入研究黄芩素诱导白血病细胞凋亡、阻碍细胞周期进展、抑制炎症反应、调控信号转导和基因转录等的分子机理，探索黄芩素克服慢性粒细胞白血病酪氨酸激酶抑制剂耐受性的潜在机制。在体外，利用克隆形成单位试验在慢性粒细胞白血病病人细胞水平测试黄芩素抗白血病疗效。同时，利用 6133/MPL W515L 细胞和 BCR-ABL 转导的原代骨髓细胞骨髓移植分别建立急性巨核细胞白血病和慢性粒细胞白血病小鼠模型，在模型小鼠个体水平验证黄芩素治疗的效果，探索黄芩素干扰白血病干/祖细胞自我更新的功能。该课题的实施将为临床应用黄芩素治疗白血病提供科学的实验依据，探索中药治疗白血病的新疗法。

急性巨核细胞白血病缺乏有效疗法，而慢性粒细胞白血病的靶向治疗面临耐药性的难题，亟需开发新疗法。黄连解毒汤辅助治疗急慢性粒细胞白血病具有良好的临床反应；前期实验研究证实组方中的有效成分黄芩素能抑制多种白血病细胞系增殖。课题组先后从四个方面围绕着该课题开展相关研究，发现黄芩素具有治疗急性T淋巴细胞白血病及急性巨核细胞白血病的作用；同时通过临床病例分析发现作为多发性骨髓瘤患者初始治疗方案，VD方案较TD方案有更高的CR及VGPR率，两种化疗方案均具备良好的总缓解率及安全性。急性ALL相关研究的文献剂量学分析提示截止2016年10月份共有10204篇ALL相关的研究发表，Blood杂志在过去的近五年内发表ALL相关文献最多，美国在ALL研究领域处于领先地位，研究者合作网络分析提示，中国学者在ALL研究领域与国外研究团队缺乏足够联系，ALL相关研究的标题信息文本挖掘提示，临床研究是ALL研究热点，ALL相关研究的被引情况分析提示，中国学者在ALL研究领域发表的高质量研究相对不足。以上研究，为治疗白血病提供了新的方向，具有深刻的意义。