Potential antitumor activity of digitoxin and user-designed analog administered to human lung cancer cells

Details

• Alternative Title:
  Biochim Biophys Acta Gen Subj
• Personal Author:
  Eldawud, Reem ; Wagner, Alixandra ; Dong, Chenbo ; Gupta, Neha ; Rojanasakul, Yon ; O’Doherty, George ; Stueckle, Todd A. ; Dinu, Cerasela Zoica
• Description:
  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.
  
  General 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.
  
  
• Subjects:
  Antineoplastic Agents Carcinoma, Non-Small-Cell Lung Cell Line, Tumor Cell Movement Cytoskeleton Digitoxin Humans Lung Neoplasms
• Keywords:
  Anti-tumor Activity Cardiac Glycosides Chemotherapy Lung Cancer Synthetic Analog Therapeutic Alternatives
• Source:
  Biochim Biophys Acta Gen Subj. 1864(11):129683
• Pubmed ID:
  32679249
• Pubmed Central ID:
  PMC7484221
• Document Type:
  Journal Article
• Funding:
  CC999999/ImCDC/Intramural CDC HHSUnited States/ ; R01 ES022968/ES/NIEHS NIH HHSUnited States/ ; U54 GM104942/GM/NIGMS NIH HHSUnited States/
• Volume:
  1864
• Issue:
  11
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:2c69cbdb4552524eef9813e37a9d9a0cd3ce9239ed44355e96f154f266de7ba5dee1fef750d58c9557951fc0b594d8a2e9fd93974d160f4155d5fe7b26012a3d
• Download URL:
  https://stacks.cdc.gov/view/cdc/93512/cdc_93512_DS1.pdf
• File Type:
  [PDF - 1.40 MB ]