Identification of arctigenin as an antitumor agent having the ability to eliminate the tolerance of cancer cells to nutrient starvation
Identification of arctigenin as an antitumor agent having the ability to eliminate the tolerance of cancer cells to nutrient starvation
复制标题
DOI：
10.1158/0008-5472.can-05-3143
复制
发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Esumi, H
中科院分区：
文献类型：
--
作者：
Awale, S;Lu, J;Esumi, H
肿瘤细胞一般增殖迅速，由于生长不受调节，血管供应不足和不适当，肿瘤细胞对必需营养物质和氧气的需求量往往超过供给量。然而，癌细胞表现出一种固有的能力，通过调节它们的能量代谢来忍受极端条件，例如以低营养和低氧供应为特征的条件。因此，靶向营养缺乏的癌细胞可能是抗癌药物开发的一种新策略。在此基础上，我们建立了一种新的筛选方法，以发现在营养剥夺条件下优先抑制癌细胞活力的抗癌药物。通过对500种日本汉布药药用植物提取物的筛选，我们发现一种ch2cl2可溶性牛蒡提取物在50 μ g/mL的浓度下，在营养剥夺条件下表现出100%的细胞毒性，而在营养丰富的条件下几乎没有细胞毒性。进一步的生物测定指导下的分离和分离导致了牛蒡素作为负责这种优先细胞毒性的主要化合物的分离；当浓度为0.01 μ g/mL时，该化合物对营养缺乏的细胞表现出100%的优先细胞毒性。此外，还发现arctigenin在裸鼠中强烈抑制PANC-1肿瘤的生长，以及几种所测试的胰腺癌细胞系的生长，这表明这种新的抗紧缩方法在癌症治疗中的可行性。对arctigenin作用机制的进一步研究发现，该化合物阻断了葡萄糖饥饿诱导的Akt活化，这是癌细胞对葡萄糖饥饿耐受的关键过程。
Tumor cells generally proliferate rapidly and the demand for essential nutrients as well as oxygen always exceeds the supply due to the unregulated growth and the insufficient and inappropriate vascular supply. However, cancer cells show an inherent ability to tolerate extreme conditions, such as that characterized by low nutrient and oxygen supply, by modulating their energy metabolism. Thus, targeting nutrient-deprived cancer cells may be a novel strategy in anticancer drug development. Based on that, we established a novel screening method to discover anticancer agents that preferentially inhibit cancer cell viability under the nutrient-deprived condition. After screening 500 medicinal plant extracts used in Japanese Kampo medicine, we found that a CH2Cl2-soluble extract of Arctium lappa exhibited 100% preferential cytotoxicity under the nutrient-deprived condition at a concentration of 50 mu g/mL with virtually no cytotoxicity under nutrient-rich condition. Further bioassay-guided fractionation and isolation led to the isolation of arctigenin as the primary compound responsible for such preferential cytotoxicity; the compound exhibited 100% preferential cytotoxicity against nutrient-deprived cells at a concentration of 0.01 mu g/mL. Furthermore, arctigenin was also found to strongly suppress the PANC-1 tumor growth in nude mice, as well as the growth of several of the tested pancreatic cancer cell lines, suggesting the feasibility of this novel antiausterity approach in cancer therapy. Further investigation of the mechanism of action of arctigenin revealed that the compound blocked the activation of Akt induced by glucose starvation, which is a key process in the tolerance exhibited by cancer cells to glucose starvation.