Cytotoxic Effects of Cardiac Glycosides in Colon Cancer Cells, Alone and in Combination with Standard Chemotherapeutic Drugs
Cytotoxic Effects of Cardiac Glycosides in Colon Cancer Cells, Alone and in Combination with Standard Chemotherapeutic Drugs
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DOI：
10.1021/np900210m
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发表时间：
2009-11-01
影响因子：
5.1
通讯作者：
Gullbo, Joachim
中科院分区：
文献类型：
--
作者：
Felth, Jenny;Rickardson, Linda;Gullbo, Joachim
据报道，心脏糖苷对几种不同类型的癌症具有细胞毒活性，但缺乏针对结直肠癌的研究。在一项旨在确定具有抗结肠癌活性的天然产物的筛选程序中，发现了几种令人感兴趣的心脏糖苷，其中五种被进一步在不同的结直肠癌细胞系和患者的原代细胞中进行了评估。活性最强的化合物为魔芋毒素(1)、齐墩果苷(4)和香豆素A(5)，而用于心脏疾病的洋地黄毒素(2)和地高辛(3)活性较低(IC50值为0.27-4.1mU/M)。选定的强心苷与四种临床相关的细胞毒性药物(5-氟尿嘧啶、奥沙利铂、顺铂、伊立替康)联合进行检测。2和奥沙利铂的联合应用显示出协同作用，包括其他高度耐药的HT29细胞株。一个ChemGPS-NP应用程序比较了抗癌药物的作用模式，发现心脏苷类药物是一个单独的簇。这些发现表明，这些物质可能通过与目前使用的抗癌药物不同的机制显示出对结直肠癌细胞株的显著活性，但其浓度通常被认为是患者血浆中无法达到的。
Cardiac glycosides have been reported to exhibit cytotoxic activity against several different cancer types, but studies against colorectal cancer are lacking. In a screening procedure aimed at identifying natural products with activity against colon cancer, several cardiac glycosides were shown to be of interest, and five of these were further evaluated in different colorectal cancer cell lines and primary cells from patients. Convallatoxin (1), oleandrin (4), and proscillaridin A (5) were identified as the most potent compounds (submicromolar IC50 values), and digitoxin (2) and digoxin (3), which are used in cardiac disease, exhibited some what lower activity (IC50 values 0.27-4.1 mu M). Selected cardiac glycosides were tested in combination with four clinically relevant cytotoxic drugs (5-fluorouracil, oxaliplatin, cisplatin, irinotecan). The combination of 2 and oxaliplatin exhibited synergism including the otherwise highly drug-resistant HT29 cell line. A ChemGPS-NP application comparing modes of action of anticancer drugs identified cardiac glycosides as a separate cluster. These findings demonstrate that such substances may exhibit significant activity against colorectal cancer cell lines, by mechanisms disparate from currently used anticancer drugs, but at concentrations generally considered not achievable in patient plasma.