基于杂气论的三氧化二砷诱导胰腺癌干细胞凋亡增效药物及机制研究

Based on the Za-qi theory, the initiator of sect of epidemic febrile disease treatment, Wu Youxing presented a treatment principle to regulate Qi causing diseases with special substances. Our study group reported at the first time worldwide that arsenic trioxide (ATO) capable of inhibiting viability of pancreatic cancer stem cells and inducing apoptosis in them via binding to Gli proteins of Sonic Hedghehog pathway. The study is designed to explore the mechanism that the drugs such as Renzhonghuang which was the recorded in the classic book entitled Zhangshi Yitong composed by doctor named Zhang Lu living in Qing dynasty, enhancing the effects of arsenic trioxide to inducing apoptosis in pancreatic cancer stem cells applying a new perspective from coordination chemistry. In this applicant study, three kinds of experiments including cellular, animal, and clinical were ready to perform to evaluate and determine the enhancing drug of ATO step by step. Molecular biochemistry analysis will be used for detecting the effects and mechanism of drugs on pancreatic cancer stem cells, and coordination chemistry method will be used for determine whether the enhancing drugs is able to form a complex with arsenic ions, meantime, the binding process of ATO to SHH-Gli1 protein within pancreatic cancer cells will be observed by confocal laser scanning microscope system. Through this study we hope to establish a treatment plan to kill pancreatic cancer stem cells composed of ATO and its enhancing drug. It's should be noted that this study is a practice under special medicine therapeutic strategy presented by Wu Youxing more than 350 years ago, and the theory about Za-qi might be enriched and developed by this study.

温病学派开创者吴有性针对杂气病因提出以"以物制气"为原则的特效药物治疗思想。我们课题组在国际上首先报道了矿物类中药砒霜或砒石的有效成分三氧化二砷可以与Sonic Hedgehog（SHH）信号通路Gli蛋白发生特异性结合，抑制胰腺癌干细胞活力并诱导其凋亡。本项目主要根据清 张璐《张氏医通》记载的人中黄散,从配位化学角度探索人中黄等药物为三氧化二砷增效的机制。项目设计了细胞、动物和临床三类实验，逐级评估确定三氧化二砷的增效应物,通过分子生物学实验分析药物治疗对胰腺癌干细胞的诱导凋亡效应与过程，采用配位化学方法检测增效药物是否可以和三价砷离子形成配合物，采用激光共聚焦显微镜技术检测增效药物是否可以促进三价砷离子与SHH-Gli蛋白在胰腺癌细胞内结合。本项研究有望确立一个由三氧化二砷与增效药物组成的靶向清除胰腺癌干细胞治疗方案。本项目是对特效药物治疗思想的实践，丰富和发展了杂气论的科学内涵。

温病学派开创者吴有性针对杂气病因提出以“以物制气”为原则的特效药物治疗思想。我们课题组在国际上首先报道了矿物类中药砒霜或砒石的有效成分三氧化二砷可以.与Sonic Hedgehog（SHH）信号通路Gli 蛋白发生特异性结合，抑制胰腺癌干细胞活力并诱导其凋亡。本项目主要根据配位化学原理，从包括中药单体活性物质在内的有机配体为三氧化二砷诱导胰腺癌干细胞凋亡发现增效药物，并探索其机制。项目开展了细胞、动物和分子生物学实验，逐级评估确定三氧化二砷的增效应物，通过分子生物学实验分析药物治疗对胰腺癌干细胞的诱导凋亡效应与过程，采用配位化学方法检测增效药物是否可以和三价砷离子形成配合物，采用分子生物学分析初步发现研究确立的砷配合物诱导胰腺癌细胞凋亡的机制可能是通过肿瘤细胞抑制蛋白酶体活性发挥效应。通过本项研究筛选了一种三氧化二砷增效药物，可以和三价砷离子形成抗肿瘤配合物，分析认为形成的三价砷配合物具有诱导胰腺癌干细胞凋亡的效应，有望由此组成一个由三氧化二砷与增效药物组成的胰腺癌临床治疗方案。本项目是对特效药物治疗思想的实践，丰富和发展了杂气论的科学内涵。