Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells.

Abstract

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 potency 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.

• Authors: Hosam A Elbaz, Todd A Stueckle, Hua-Yu Leo Wang, George A O'Doherty, David T Lowry, Linda M Sargent, Liying Wang, Cerasela Zoica Dinu, Yon Rojanasakul
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 258 Issue 1 Pg. 51-60 (Jan 01 2012) ISSN: 1096-0333 [Electronic] United States
• PMID: 22037315 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• CCNB1 protein, human
• Cyclin B1
• D6-MA compound
• Cytochromes c
• Digitoxin
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1
• Caspase 9
• Sodium-Potassium-Exchanging ATPase
• Rhamnose

Topics

• Antineoplastic Agents (pharmacology)
• Caspase 9 (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Checkpoint Kinase 1
• Cyclin B1 (analysis)
• Cytochromes c (analysis)
• Digitoxin (analogs & derivatives, pharmacology)
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Protein Kinases (analysis)
• Rhamnose (analogs & derivatives, pharmacology)
• Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors)