Potential antitumor activity of digitoxin and user-designed analog administered to human lung cancer cells.,Biochimica et Biophysica Acta (BBA) - General Subjects

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Potential antitumor activity of digitoxin and user-designed analog administered to human lung cancer cells.
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2020-07-15 , DOI: 10.1016/j.bbagen.2020.129683
Reem Eldawud ₁ , Alixandra Wagner ₁ , Chenbo Dong ₁ , Neha Gupta ₁ , Yon Rojanasakul ₂ , George O'Doherty ₃ , Todd A Stueckle ₄ , Cerasela Zoica Dinu ₁

Affiliation

Background

Cardiac glycosides (CGs), such as digitoxin, are traditionally used for treatment of congestive heart failure; recently they also gained attention for their anticancer properties. Previous studies showed that digitoxin and a synthetic L-sugar monosaccharide analog treatment decreases cancer cell proliferation, increases apoptosis, and pro-adhesion abilities; however, no reports are available on their potential to alter lung cancer cell cytoskeleton structure and reduce migratory ability. Herein, we investigated the anticancer effects of digitoxin and its analog, digitoxigenin-α-L-rhamnoside (D6MA), to establish whether cytoskeleton reorganization and reduced motility are drug-induced cellular outcomes.

Methods

We treated non-small cell lung carcinoma cells (NSCLCs) with sub-therapeutic, therapeutic, and toxic concentrations of digitoxin and D6MA respectively, followed by both single point and real-time assays to evaluate changes in cellular gene and protein expression, adhesion, elasticity, and migration.

Results

Digitoxin and D6MA induced a decrease in matrix metalloproteinases expression via altered focal adhesion signaling and a suppression of the phosphoinositide 3-kinases / protein kinase B pathway which lead to enhanced adhesion, altered elasticity, and reduced motility of NSCLCs. Global gene expression analysis identified dose-dependent changes to nuclear factor kappa-light-chain-enhancer, epithelial tumor, and microtubule dynamics signaling.

Conclusions

Our study demonstrates that digitoxin and D6MA can target antitumor signaling pathways to alter NSCLC cytoskeleton and migratory ability to thus potentially reduce their tumorigenicity.

Significance

Discovering signaling pathways that control cancer's cell phenotype and how such pathways are affected by CG treatment will potentially allow for active usage of synthetic CG analogs as therapeutic agents in advanced lung conditions.

中文翻译：

洋地黄毒苷和用户设计的类似物对人肺癌细胞的潜在抗肿瘤活性。

背景

强心苷 (CG)，例如洋地黄毒苷，传统上用于治疗充血性心力衰竭；最近，它们也因其抗癌特性而受到关注。先前的研究表明，洋地黄毒苷和合成的 L-糖单糖类似物治疗可降低癌细胞增殖、增加细胞凋亡和促粘附能力；然而，没有关于它们改变肺癌细胞骨架结构和降低迁移能力的潜力的报告。在此，我们研究了洋地黄毒苷及其类似物洋地黄毒苷-α-L-鼠李糖苷（D6MA）的抗癌作用，以确定细胞骨架重组和运动性降低是否是药物诱导的细胞结果。