Human breast tumor cells are more resistant to cardiac glycoside toxicity than non-tumorigenic breast cells.
Human breast tumor cells are more resistant to cardiac glycoside toxicity than non-tumorigenic breast cells.
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DOI：
10.1371/journal.pone.0084306
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kaplan JH
中科院分区：
文献类型：
--
作者：
Clifford RJ;Kaplan JH
强心性类固醇(CTS)是Na，K-ATPase活性的特异性抑制剂，已广泛用于治疗心功能不全。最近的研究表明，低水平的内源性CTS并不抑制Na，K-ATPase的活性，但在调节血压、诱导细胞激酶活性和促进细胞活力方面发挥作用。较高的CTS浓度抑制Na，K-ATPase活性，并可诱导活性氧产生、生长停滞和细胞死亡。CTS被认为是癌症治疗的潜在新疗法，因为它们被证明可以限制肿瘤细胞的生长。然而，缺乏关于肿瘤细胞和可比非肿瘤细胞的相对毒性的信息。我们已经研究了CTS化合物哇巴因、洋地黄毒素和蟾酥对细胞生长和存活的影响，这些细胞系表现出从非癌到恶性的全谱表型。我们发现CTS在所有被测试的细胞系中抑制膜Na，K-ATPase活性的效果相同，而不考虑转移潜能。相比之下，非肿瘤细胞和肿瘤细胞对药物的反应是不同的。哇巴因对非肿瘤乳腺细胞的增殖抑制作用更强，与恶性或癌基因转染者相比，可导致更广泛的细胞凋亡。在肿瘤细胞中，哇巴因的作用伴随着抗凋亡的ERK1/2的激活。然而，ERK1/2或Src的抑制并不能使肿瘤细胞对CTS细胞毒敏感，提示其他机制对肿瘤细胞具有保护作用。与非肿瘤细胞相比，乳腺肿瘤细胞对CTS的敏感性降低，表明CTS不是很好的癌症治疗候选药物。
Cardiotonic steroids (CTS), specific inhibitors of Na,K-ATPase activity, have been widely used for treating cardiac insufficiency. Recent studies suggest that low levels of endogenous CTS do not inhibit Na,K-ATPase activity but play a role in regulating blood pressure, inducing cellular kinase activity, and promoting cell viability. Higher CTS concentrations inhibit Na,K-ATPase activity and can induce reactive oxygen species, growth arrest, and cell death. CTS are being considered as potential novel therapies in cancer treatment, as they have been shown to limit tumor cell growth. However, there is a lack of information on the relative toxicity of tumor cells and comparable non-tumor cells. We have investigated the effects of CTS compounds, ouabain, digitoxin, and bufalin, on cell growth and survival in cell lines exhibiting the full spectrum of non-cancerous to malignant phenotypes. We show that CTS inhibit membrane Na,K-ATPase activity equally well in all cell lines tested regardless of metastatic potential. In contrast, the cellular responses to the drugs are different in non-tumor and tumor cells. Ouabain causes greater inhibition of proliferation and more extensive apoptosis in non-tumor breast cells compared to malignant or oncogene-transfected cells. In tumor cells, the effects of ouabain are accompanied by activation of anti-apoptotic ERK1/2. However, ERK1/2 or Src inhibition does not sensitize tumor cells to CTS cytotoxicity, suggesting that other mechanisms provide protection to the tumor cells. Reduced CTS-sensitivity in breast tumor cells compared to non-tumor cells indicates that CTS are not good candidates as cancer therapies.