Autophagy-Induced Apoptosis in Lung Cancer Cells by a Novel Digitoxin Analog.
Autophagy-Induced Apoptosis in Lung Cancer Cells by a Novel Digitoxin Analog.
复制标题
DOI：
10.1002/jcp.25129
复制
发表时间：
2016-04
影响因子：
5.6
通讯作者：
Iyer AK
中科院分区：
文献类型：
--
作者：
Kulkarni YM;Kaushik V;Azad N;Wright C;Rojanasakul Y;O'Doherty G;Iyer AK
我们已经合成了一种新的洋地黄毒苷衍生物，称为“MonoD”，它在肺癌细胞中表现出比洋地黄毒苷更高的细胞毒性作用。我们的数据显示，在MonoD处理的1小时内，H460细胞显示出增加的氧化应激，增加的自噬空泡形成，以及增加的促自噬标志物Beclin-1和LC 3-II的表达。用MnTBAP（一种超氧化物清除剂）预处理的细胞不仅降低了超氧化物的产生，而且具有较低水平的LC 3-II和Beclin-1。肺癌细胞中MonoD诱导的细胞凋亡的延长治疗。我们研究了Akt和Bcl 2的MonoD依赖性调节，Akt和Bcl 2是已知的自噬和凋亡调节蛋白。Bcl 2和Akt的分子和药理学抑制剂，当与MonoD组合时，与单独的MonoD相比，导致LC 3-II和Beclin-1的更高表达，表明这些蛋白质在MonoD依赖性自噬中的抑制作用。用自噬抑制剂预处理细胞抑制了MonoD的凋亡潜力，证实了早期自噬通量对驱动凋亡是重要的。靶向多个途径（如自噬和凋亡）的治疗实体（如MonoD）可以证明优于具有单峰作用基础的当前疗法，并且可以驱动持续的肿瘤消退，这是非常期望的。
We have synthesized a novel derivative of Digitoxin, termed “MonoD”, which demonstrates cytotoxic effects in lung cancer cells with much higher potency as compared to Digitoxin. Our data show that within 1 h of MonoD treatment, H460 cells showed increased oxidative stress, increased formation of autophagic vacuoles, and increased expression of pro-autophagic markers Beclin-1 and LC3-II. Cells pretreated with MnTBAP, a superoxide scavenger not only lowered superoxide production, but also had lower levels of LC3-II and Beclin-1. Prolonged treatment with MonoD-induced apoptosis in lung cancer cells. We investigated MonoD-dependent regulation of Akt and Bcl2, proteins that are known regulators of both autophagy and apoptosis. Molecular and pharmacologic inhibitors of Bcl2 and Akt, when combined with MonoD, led to higher expression of LC3-II and Beclin-1 as compared to MonoD alone, suggesting a repressive effect for these proteins in MonoD-dependent autophagy. Pretreatment of cells with an autophagy inhibitor repressed the apoptotic potential of MonoD, confirming that early autophagic flux is important to drive apoptosis. Therapeutic entities such as MonoD that target multiple pathways such as autophagy and apoptosis may prove advantageous over current therapies that have unimodal basis for action and may drive sustained tumor regression, which is highly desirable.