基于Warburg效应探究破血药化瘀散结抑制肿瘤转移的分子基础

POXUE herbs were used widely in clinic for treatment of cancer. However, it is unconfirmed whether it inhibits tumor metastasis or facilitates it. The project is to elucidate how poxue herbs affect tumor metastasis based on Warburg effect and its molecular mechanism. Firstly, the traditional theory regards the solid tumor as the severe blood stasis syndrome which is relieved by removing the blood stasis and dissolving the microvessels. So the intrinsic mechanism that poxue herbs remove the stasis in tumor issue is to disturb the way of energy metabolism----- Aerobic glycolysis, breaking the specified circumstance for tumor growth and metastasis. Secondly, cumulative data justified that angiogenesis mediating the aerobic glycolysis and tumor metastasis was inhibited by poxue herbs. Finally, inhibition of aerobic glycolysis is consistent with the macroscopic therapeutic theory of traditional medicine. Thus, it is concluded that the poxue herbs inhibit tumor metastasis and its molecular mechanism is related to the course of aerobic glycolysis. The project is to find out how poxue herbs affect the rate-limiting enzyme (HK, PFK, PKM)-mediated the course of aerobic glycolysis, resulting in the alteration of adhension, motility and migration in cancer cells. Research significance: confirm the inhibitory effect of poxue herbs on tumor metastasis and its molecular mechanism to help the physician use poxue herbs correctly, and find the prospective active compounds for inhibition of metastasis.

破血药临床抗肿瘤应用广，但对肿瘤转移是促进还是抑制争论不一。本项目拟结合Warburg效应的有氧糖酵解理论（肿瘤细胞的特征性能量代谢方式）揭示破血药化瘀散结对肿瘤转移的影响及其分子机制。首先，中医认为肿瘤属于典型的血瘀证，治以化瘀散结。则破血药化瘀散结去肿瘤血瘀的实质应是干扰肿瘤组织的有氧糖酵解能量代谢模式，破坏其特定微环境；其次，越来越多的数据证实，破血药对有氧糖酵解促进肿瘤转移的关键环节血管生成有抑制作用；最后，干扰肿瘤能量代谢符合中医治本的治病原则。因此认为：破血药抑制肿瘤转移，其分子机制与有氧糖酵解能量代谢及调控过程有关。研究内容：探究破血药影响己糖激酶、6磷酸果糖激酶或丙酮酸激酶等糖代谢限速酶介导的有氧糖酵解能量代谢及调控过程，及其与肿瘤细胞粘附、运动和迁移之间的关系。意义：明确破血药抑制肿瘤转移及其分子机制，消除临床使用疑虑；确定有抑制肿瘤转移作用并有新药创制前景的效应成分。

破血药临床抗肿瘤应用广，但对肿瘤转移是促进还是抑制争论不一。本项目结合Warburg效应的有氧糖酵解理论，考察破血药化瘀散结对肿瘤转移的影响并揭示其分子作用机理。.项目首先利用大数据信息分析手段系统筛选了破血药莪术（92）、三棱（28）、斑蝥（10）和水蛭（31）中的总共161种成分及其可能的与抗肿瘤及肿瘤转移相关的靶点，筛选出的10余种成分经过体内外的实验验证，证实莪术中的β-榄香烯和莪术醇成分、三棱的山奈酚成分、斑蝥中的斑蝥素和水蛭中的水蛭素等成分均显现出明显的抗肿瘤转移作用。分子机理研究显示，β-榄香烯抑制PKM2二、四聚体的转化和入核、降低PK活性，从而抑制细胞有氧糖酵解而抗乳腺癌转移；莪术醇抑制HK2介导的磷酸戊糖途径发挥抗乳腺癌转移作用；斑蝥素抑制GLUT1介导PKM2调控环路影响乳腺癌细胞糖酵解过程，促使其向正常细胞代谢方式转化而抗肿瘤转移；山奈酚通过抑制GSK3β的磷酸化减少HK2与VDAC的结合，从而抑制HK的活性，降低黑色素瘤的糖酵解代谢水平，达到抑制肿瘤转移的作用。.综上所述，1）破血药莪术、三棱、斑蝥和水蛭等均表现明显的抗肿瘤转移作用，且含有抗转移的有效成分，这是其抗肿瘤转移的物质基础；2）破血药有效成分的抗肿瘤转移作用大多与影响有氧糖酵解相关；3）破血药不同成分影响有氧糖酵解的具体环节机制不同，体现了中药多靶点、多途径等特点；4）血瘀证可解释为一种伴有区域葡萄糖能量代谢异常的有氧糖酵解过程，而非氧化磷酸化过程；5）破血药化瘀散结功效的现代理论可理解为：破血药通过干扰细胞有氧糖酵解、影响细胞糖代谢，进而发挥化瘀散结的功效； .本项目的实施可消除临床使用破血药会引起肿瘤转移的疑虑，对进一步推广临床破血药抗肿瘤的使用有很好的指导意义。创新血瘀证的现代理论定义：一种伴有区域葡萄糖能量代谢异常的有氧糖酵解过程。这在活血化瘀治则治法的研究方面有很好的学术价值。上述重点研究成分在抗肿瘤转移的临床方面有很好的转化潜力，尤其是联合使用的前景更好。

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