Kok Stanton Hon Lung, Chui Chung Hin, Lam Wing Sze, Chen Jien, Tang Johnny Cheuk On, Lau Fung Yi, Cheng Gregory Yin Ming, Wong Raymond Siu Ming, Chan Albert Sun Chi
Anti-cancer Research Center, Shenzhen Key Laboratory of Chinese Medicine and Molecular Pharmacology and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, P.R. China.
Int J Mol Med. 2006 Jan;17(1):151-7.
Cantharidin isolated from Mylabris caraganae and other insects has been used as an anti-cancer drug in China for many years. However, its toxicity on the renal system and suppression effect on bone marrow limits its usage clinically. Based on the core structure of cantharidin, we have chemically synthesized two cantharidin analogues (compounds 2 and 3). The cytotoxic activity of these analogues was demonstrated on the Hep3B hepatocellular carcinoma, MDA-MB231 breast cancer, A549 non-small cell lung carcinoma and KG1a acute myelogenous leukaemia (AML) cell lines by monitoring the intracellular adenosine triphosphate level. Morphological changes in these cancer cell lines, including cell shrinkage and loss of adherent potential, were readily observed. By making use of the KG1a AML cells as a test model, we further found that mitochondrial membrane potential depolarization and reduction of intracellular bcl-2 anti-apoptotic protein level were involved. These resulted in the activation of caspase 3 protease activity and oligonucleosomal length DNA fragment formation as detected by both time resolved fluorescence technology-based caspase activity assay and TdT-mediated dUTP nick end-labelling assay.
从豆芫菁及其他昆虫中分离得到的斑蝥素在中国作为抗癌药物已使用多年。然而，其对肾脏系统的毒性以及对骨髓的抑制作用限制了它在临床上的应用。基于斑蝥素的核心结构，我们化学合成了两种斑蝥素类似物（化合物2和3）。通过监测细胞内三磷酸腺苷水平，在Hep3B肝癌细胞、MDA - MB231乳腺癌细胞、A549非小细胞肺癌细胞和KG1a急性髓性白血病（AML）细胞系上证实了这些类似物的细胞毒性活性。很容易观察到这些癌细胞系中的形态学变化，包括细胞收缩和贴壁能力丧失。以KG1a AML细胞作为测试模型，我们进一步发现其涉及线粒体膜电位去极化和细胞内bcl - 2抗凋亡蛋白水平降低。通过基于时间分辨荧光技术的半胱天冬酶活性测定和TdT介导的dUTP缺口末端标记测定检测到，这些导致了半胱天冬酶3蛋白酶活性的激活和寡核小体长度DNA片段的形成。
