Pro-apoptotic and cytostatic activity of naturally occurring cardenolides
Pro-apoptotic and cytostatic activity of naturally occurring cardenolides
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DOI：
10.1007/s00280-009-0929-5
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发表时间：
2009-09-01
影响因子：
3
通讯作者：
Belisario, Maria Antonietta
中科院分区：
文献类型：
--
作者：
Bloise, Elena;Braca, Alessandra;Belisario, Maria Antonietta
Cardenolides是类固醇糖苷，已知其通过抑制Na+/K+-ATP酶发挥强心作用。这些化合物中的几种也显示出具有抗肿瘤潜力。本工作的目的是表征从杠柳（Periploca graeca L.）在U937（单核细胞白血病）和PC 3（前列腺腺癌）中测试化合物的促凋亡和细胞抑制作用。流式细胞术和WB检测细胞凋亡和细胞周期障碍的特征。杠柳苷和杠柳苷是最具活性的化合物，杠柳苷比对照化合物哇巴因更有效。这两种Cardenolides的细胞数量的减少是由于在PC 3细胞中主要是半胱天冬酶依赖性凋亡途径的激活，而在U937细胞中诱导细胞周期障碍而没有广泛的细胞死亡。有趣的是，杠柳素，在细胞生长抑制，但非细胞毒性剂量，被证明是敏感的U937细胞TRAIL. Together，我们的数据概述，强心苷是有前途的抗癌药物，并有助于新的天然强心苷的鉴定，以获得化学修饰的非心脏活性/低毒性的衍生物，增强抗癌效力。
Cardenoliddes are steroid glycosides which are known to exert cardiotonic effects by inhibiting the Na+/K+-ATPase. Several of these compounds have been shown also to possess anti-tumor potential. The aim of the present work was the characterization of the tumor cell growth inhibition activity of four cardenolides, isolated from Periploca graeca L., and the mechanisms underlying such an effect.The pro-apoptotic and cytostatic effect of the compounds was tested in U937 (monocytic leukemia) and PC3 (prostate adenocarcinoma). Characterization of apoptosis and cell cycle impairment was obtained by cytofluorimetry and WB.Periplocymarin and periplocin were the most active compounds, periplocymarin being more effective than the reference compound ouabain. The reduction of cell number by these two cardenolides was due in PC3 cells mainly to the activation of caspase-dependent apoptotic pathways, while in U937 cells to the induction of cell cycle impairment without extensive cell death. Interestingly, periplocymarin, at cytostatic but non-cytotoxic doses, was shown to sensitize U937 cells to TRAIL.Taken together, our data outline that cardiac glycosides are promising anticancer drugs and contribute to the identification of new natural cardiac glycosides to obtain chemically modified non-cardioactive/low toxic derivatives with enhanced anticancer potency.