组织凝血因子III启动血管生成开关对丹参抑制休眠肿瘤恶变的作用机制

Salvia, one of the traditional Chinese medicine (TCM) promoting blood circulation and removing blood stasis, has been one of the most frequent used medicine in TCM anticancer prescriptions. We have confirmed the inhibitory effect of salvia in cancer metastasis and the inhibitory effect is closely related with salvia’s effect on angiogenesis. Active constituents of salvia contain the hydrophilic phenolic acids and the lipophilic tanshinones which have different targets. Tumor development and progression is dynamic and complex with multiple regulators involved individually. The effect and the mechanistic link of salvia on the early stages of tumor development, especially on the tumor dormancy progression to malignancy is still unveil. In this study, we will employ molecular cell biology experimental techniques such as qPCR, western blot, immunofluorescent labeling to determine and analyze the effect of multiple groups of treatment on the malignant transformation of dormant tumors using cell and animal models. The treatments include the natural ratio of salvia active ingredients A, the hydrophilic phenolic acids B, the lipophilic tanshinones C, and the A-B and A-C constituents obtained using the selective component knockout strategy. Finally, we will analyze whether the hydrophilic phenolic acids and the lipophilic tanshinones have more synergistic effect than additive effect by using mathematical pharmacology method. Our study will provide experimental evidence for clinical application of salvia.

活血化瘀药丹参在抗癌方中应用频率很高。课题组前期工作确定了丹参的抗肿瘤转移作用，其机制与调控肿瘤血管生成密切相关，并且水溶性丹酚酸类成分与脂溶性丹参酮类作用靶点不同。然而肿瘤的发生发展是动态、复杂的过程，各阶段的发生发展调控机制大相径庭，对于丹参在肿瘤发生发展早期特别是休眠肿瘤恶性转变这一过程的作用及机制，目前鲜有报道。本课题拟从组织凝血因子III启动的血管生成开关作为研究切入点，利用细胞、动物模型，采用qPCR, western blot, 荧光免疫标记等分子细胞生物学等实验技术手段，研究丹参活性成分天然配比A、丹酚酸类成分B、丹参酮类成分C，以及利用选择性成分敲除策略获得的A-B和A-C成分组，对休眠肿瘤恶性转变的调节作用及分子机制。最后，分析丹参两类组分是否产生大于加和的协同作用，从新的视角为临床应用丹参提供支撑。

活血化瘀药丹参在抗癌方中应用频率很高。课题组前期工作确定了丹参的抗肿瘤转移作用 ，其机制与调控肿瘤血管生成密切相关，并且水溶性丹酚酸类成分与脂溶性丹参酮类作用靶点不同。然而肿瘤的发生发展是动态、复杂的过程，各阶段的发生发展调控机制大相径庭，对于丹参在肿瘤发生发展早期特别是休眠肿瘤恶性转变这一过程的作用及机制，目前鲜有报道。本课题从组织凝血因子III启动的血管生成开关作为研究切入点，利用细胞、动物模型，采用qPCR, western blot, 荧光免疫标记等分子细胞生物学等实验技术手段，研究丹参活性成分对休眠肿瘤恶变的药效作用。我们发现：1. 脂溶性成分丹参酮IIA可以抑制自发乳腺癌小鼠模型从腺癌向早期癌的发展，而水溶性成分丹酚酸B不具有此种效应。丹参水溶性成分与脂溶性成分的作用阶段存在差异。2. 在乳腺癌、皮肤癌、肾透明细胞癌、结直肠癌等动物模型上，对潜力成分进行筛选及药效评价，发现了番茄红素(lycopene)、根薯酮内酯AJ (Taccalonolide AJ)等活性成分对肿瘤发生发展有抑制作用。3. 细胞内氧化还原平衡是肿瘤发生发展阶段的重要调控机制，Nrf2的活化、转录入核可以作为药物干预的靶点。番茄红素可以通过激活自噬相关蛋白p62, 促进Keap1蛋白的降解，活化Nrf2发挥干预皮肤癌恶性发展的化学预防作用。