Actein inhibits the Na+-K+-ATPase and enhances the growth inhibitory effect of digitoxin on human breast cancer cells.

Abstract

The Na+K+-ATPase is a known target of cardiac glycosides such as digitoxin and ouabain. We determined that the enzyme also is a target of the structurally-related triterpene glycoside actein, present in the herb black cohosh. Actein's inhibition of Na+-K+-ATPase activity was less potent than that of digitoxin, but actein potentiated digitoxin's inhibitory effect on Na+-K+-ATPase activity and MDA-MB-453 breast cancer cell growth. We observed different degrees of signal amplification for the two compounds. Actein's inhibitory effect on ATPase activity was amplified 2-fold for cell growth inhibition, whereas digitoxin's signal was amplified 20-fold. Actein induced a biphasic response in proteins downstream of ATPase: low dose and short duration of treatment upregulated NF-kappaB promoter activity, p-ERK, p-Akt and cyclin D1 protein levels, whereas higher doses and longer exposure inhibited these activities. Actein and digitoxin may be a useful synergistic combination for cancer chemoprevention and/or therapy.

• Authors: Linda Saxe Einbond, Masahito Shimizu, Hangbao Ma, Hsan-Au Wu, Sarah Goldsberry, Serge Sicular, Maya Panjikaran, Giannicola Genovese, Erica Cruz
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 375 Issue 4 Pg. 608-13 (Oct 31 2008) ISSN: 1090-2104 [Electronic] United States
• PMID: 18755149 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Drugs, Chinese Herbal
• Enzyme Inhibitors
• NF-kappa B
• Saponins
• Triterpenes
• Digitoxin
• Mitogen-Activated Protein Kinase 1
• Sodium-Potassium-Exchanging ATPase
• actein

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (enzymology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Digitoxin (pharmacology)
• Drug Synergism
• Drugs, Chinese Herbal (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Humans
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• NF-kappa B (genetics)
• Promoter Regions, Genetic (drug effects)
• RNA Interference
• Saponins (pharmacology)
• Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors)
• Triterpenes (pharmacology)