Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells.
Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells.
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DOI：
10.1016/j.taap.2011.10.007
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发表时间：
2012-01-01
影响因子：
3.8
通讯作者：
Rojanasakul, Yon
中科院分区：
文献类型：
--
作者：
Elbaz, Hosam A.;Stueckle, Todd A.;Wang, Hua-Yu Leo;O'Doherty, George A.;Lowry, David T.;Sargent, Linda M.;Wang, Liying;Dinu, Cerasela Zoica;Rojanasakul, Yon
洋地黄毒苷抑制人非小细胞肺癌（NCI-H460）细胞生长和诱导细胞凋亡的机制尚不清楚。了解洋地黄毒苷或衍生物类似物如何在低于治疗相关浓度时诱导其细胞毒性作用，将有助于设计和开发新的、更安全和更有效的抗癌药物。在这项研究中，NCI-H460细胞用洋地黄毒苷和合成类似物D 6-MA处理，以确定其抗癌活性。使用不同浓度的洋地黄毒苷和D 6-MA，并测定细胞形态、活力、细胞周期和蛋白表达的后续变化。洋地黄毒苷和D 6-MA均能诱导NCI-H460细胞凋亡，并呈剂量依赖性，D 6-MA诱导凋亡的能力是洋地黄毒苷的5倍。相比之下，与NCI-H460细胞相比，非致瘤性永生化支气管和小气道上皮细胞显示出显著更低的凋亡敏感性，这表明洋地黄毒苷和D 6-MA对NSCLC都具有选择性。地高辛和D 6-MA处理后，NCI-H460细胞阻滞于G（2）/M期。关键G2/M检查点调节蛋白的治疗后评价确定了细胞周期蛋白B1/cdc 2复合物和生存素的下调。此外，Chk 1/2和p53相关蛋白质经历了下调，这表明了一种不依赖于p53的细胞周期停滞机制。总之，洋地黄毒苷和D 6-MA通过细胞凋亡或细胞周期停滞对NCI-H460细胞发挥抗癌作用，其中D 6-MA显示出相对于洋地黄毒苷至少5倍的效力。
Mechanisms of digitoxin-inhibited cell growth and induced apoptosis in human non-small cell lung cancer (NCI-H460) cells remain unclear. Understanding how digitoxin or derivate analogs induce their cytotoxic effect below therapeutically relevant concentrations will help in designing and developing novel, safer and more effective anti-cancer drugs. In this study, NCI-H460 cells were treated with digitoxin and a synthetic analog D6-MA to determine their anti-cancer activity. Different concentrations of digitoxin and D6-MA were used and the subsequent changes in cell morphology, viability, cell cycle, and protein expressions were determined. Digitoxin and D6-MA induced dose-dependent apoptotic morphologic changes in NCI-H460 cells via caspase-9 cleavage, with D6-MA possessing 5-fold greater potentcy than digitoxin. In comparison, non-tumorigenic immortalized bronchial and small airway epithelial cells displayed significantly less apoptotic sensitivity compared to NCI-H460 cells suggesting that both digitoxin and D6-MA were selective for NSCLC. Furthermore, NCI-H460 cells arrested in G(2)/M phase following digitoxin and D6-MA treatment. Post-treatment evaluation of key G2/M checkpoint regulatory proteins identified down-regulation of cyclin B1/cdc2 complex and survivin. Additionally, Chk1/2 and p53 related proteins experienced down-regulation suggesting a p53-independent cell cycle arrest mechanism. In summary, digitoxin and D6-MA exert anti-cancer effects on NCI-H460 cells through apoptosis or cell cycle arrest, with D6-MA showing at least 5-fold greater potency relative to digitoxin.
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影响因子：
4.2
作者：
Wang, Hua-Yu Leo;Rojanasakul, Yon;O'Doherty, George A.
通讯作者：
O'Doherty, George A.
影响因子：
3.6
作者：
Kometiani, P;Liu, LJ;Askari, A
通讯作者：
Askari, A
影响因子：
5.1
作者：
López-Ládzaro, M;Pastor, N;Cortés, F
通讯作者：
Cortés, F
影响因子：
4.7
作者：
Piao, CQ;Liu, L;Hei, TK
通讯作者：
Hei, TK
影响因子：
11.5
作者：
Mita, Alain C.;Mita, Monica M.;Giles, Francis J.
通讯作者：
Giles, Francis J.