Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells |
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Authors: | Elbaz Hosam A Stueckle Todd A Wang Hua-Yu Leo O'Doherty George A Lowry David T Sargent Linda M Wang Liying Dinu Cerasela Zoica Rojanasakul Yon |
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Affiliation: | a Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506, USAb Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USAc Department of Chemical Engineering, West Virginia University, Morgantown, WV 26506, USAd National Institute for Occupational Safety and Health, Morgantown, WV26506, USA |
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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. |
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Keywords: | Digitoxin D6-MA analog Increased potency Sub-therapeutic concentrations Anti-cancer drugs |
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