Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells.
Elbaz-HA; Stueckle-TA; Wang-H-Y; O'Doherty-G; Lowry-DT; Sargent-LM; Wang-L; Dinu-CZ; Rojanasakul-Y
Toxicol Appl Pharmacol 2012 Jan; 258(1):51-60
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.
Lung; Lung-cancer; Lung-cells; Lung-disease; Toxins; Cytology; Cytotoxic-effects; Cytotoxins; Cell-function; Cell-growth; Cellular-reactions; Antitumor-agents; Antineoplastic-agents; Proteins; Cell-morphology; Laboratory-testing; Therapeutic-agents;
Author Keywords: Digitoxin; D6-MA analog; Increased potency; Sub-therapeutic concentrations; Anti-cancer drugs
Y. Rojanasakul, Department of Basic Pharmaceutical Sciences, West Virginia University, PO Box 9530, 1 Medical Center Drive, Morgantown, WV 26506, USA
Toxicology and Applied Pharmacology