Actein inhibits the Na+-K+-ATPase and enhances the growth inhibitory effect of digitoxin on human breast cancer cells.
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.
Einbond
Linda Saxe
LS
Department of Rehabilitation Medicine, College of Physicians and Surgeons, Columbia University, HHSC-1508, 701 W. 168th Street, New York, NY 10032, USA. le2012@columbia.edu
Shimizu
Masahito
M
Ma
Hangbao
H
Wu
Hsan-Au
HA
Goldsberry
Sarah
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Sicular
Serge
S
Panjikaran
Maya
M
Genovese
Giannicola
G
Cruz
Erica
E