Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients
Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients
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DOI：
10.1021/np050226l
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发表时间：
2005-11-01
影响因子：
5.1
通讯作者：
Cortés, F
中科院分区：
文献类型：
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作者：
López-Ládzaro, M;Pastor, N;Cortés, F
强心苷洋地黄毒苷 (1) 和地高辛 (3) 多年来一直用于治疗心脏病。在此期间，一些报告表明洋地黄可能在肿瘤医学中使用。评估了洋地黄毒苷 (1) 的几种类似物在三种人类癌细胞系中的生长抑制活性；这项研究表明洋地黄毒苷 (1) 是最活跃的化合物，并揭示了一些可能在这些药物的生长抑制活性中发挥作用的结构特征。 1 (3-33 nM) 的 IC50 值处于或低于接受该糖苷的心脏病患者血浆中观察到的浓度范围 (20-33 nM)。肾腺癌细胞系 (TK-10) 对该药物过敏，洋地黄毒苷对这些细胞的毒性是通过细胞凋亡介导的。体外实验表明，30 nM 的 1 可诱导 DNA-拓扑异构酶 II 可裂解复合物的水平类似于依托泊苷，依托泊苷是一种广泛用于癌症化疗的拓扑异构酶 II 毒物。使用个体细胞检测 TARDIS，暴露于 1 30 分钟的细胞显示出较低但具有统计学意义的 DNA-拓扑异构酶 II 可裂解复合物水平；然而，这些复合物在暴露 24 小时后消失。
The cardiac glycosides digitoxin (1) and digoxin (3) have been used in cardiac diseases for many years. During this time several reports have suggested the possible use of digitalis in medical oncology. Several analogues of digitoxin (1) were evaluated for growth inhibition activity in three human cancer cell lines; this study showed that digitoxin (1) was the most active compound and revealed some structural features that may play a role in the growth inhibition activity of these drugs. The IC50 values for 1 (3-33 nM) were within or below the concentration range seen in the plasma of patients with cardiac disease receiving this glycoside (20-33 nM). A renal adenocarcinoma cancer cell line (TK-10) was hypersensitive to this drug, and digitoxin toxicity on these cells was mediated by apoptosis. In vitro experiments showed that 1 at 30 nM induced levels of DNA-topoisomerase II cleavable complexes similar to etoposide, a topoisomerase II poison widely used in cancer chemotherapy. Using the individual cell assay TARDIS, cells exposed to 1 for 30 min showed low but statistically significant levels of DNA-topoisomerase II cleavable complexes; however these complexes disappeared after 24 h exposure.