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

Details

• Personal Author:
  Dinu CZ ; Elbaz HA ; Lowry DT ; O'Doherty G ; Rojanasakul Y ; Sargent LM ; Stueckle, Todd A. ; Wang H-Y ; Wang L
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Antineoplastic Agents Cytology Cytotoxins Hazardous Substances Laboratories Lung Lung Diseases Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Safety

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• Keywords:
  Anti-cancer Drugs Antineoplastic-agents Antitumor-agents Author Keywords: Digitoxin Cell-function Cell-growth Cell-morphology Cellular-reactions Cytotoxic-effects D6-MA Analog Increased Potency Laboratory-testing Lung-cancer Lung-cells Lung-disease Proteins Sub-therapeutic Concentrations Therapeutic-agents Toxins

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• ISSN:
  0041-008X
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Massachusetts ; OSHA Region 1 ; OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  51-60
• Volume:
  258
• Issue:
  1
• NIOSHTIC Number:
  nn:20039869
• Citation:
  Toxicol Appl Pharmacol 2012 Jan; 258(1):51-60
• Contact Point Address:
  Y. Rojanasakul, Department of Basic Pharmaceutical Sciences, West Virginia University, PO Box 9530, 1 Medical Center Drive, Morgantown, WV 26506, USA
• Federal Fiscal Year:
  2012
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Toxicology and Applied Pharmacology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:26cd02f5c07cfcea075d5a55e890a0311b6fe9b352537c90b25674f1d87b4e021b6611ddd731f8c453ab44083e721da0657d27cc36bcd8b4b44b9b0d94feb27a
• Download URL:
  https://stacks.cdc.gov/view/cdc/192934/cdc_192934_DS1.pdf
• File Type:
  [PDF - 1.37 MB ]