The Cytotoxic Cardiac Glycoside (-)-Cryptanoside A from the Stems of Cryptolepis dubia and Its Molecular Targets

A cardiac glycoside epoxide, (-)-cryptanosideA (1), was isolated from the stems of Cryptolepisdubia collected in Laos, for which the complete structurewas confirmedby analysis of its spectroscopic and single-crystal X-ray diffractiondata, using copper radiation at a low temperature. This cardiac glycosideepoxide exhibited potent cytotoxicity against several human cancercell lines tested, including HT-29 colon, MDA-MB-231 breast, OVCAR3and OVCAR5 ovarian cancer, and MDA-MB-435 melanoma cells, with theIC(50) values found to be in the range 0.1-0.5 & mu;M,which is comparable with that observed for digoxin. However, it exhibitedless potent activity (IC50 1.1 & mu;M) against FT194benign/nonmalignant human fallopian tube secretory epithelial cellswhen compared with digoxin (IC50 0.16 & mu;M), indicatingits more selective activity toward human cancer versus benign/nonmalignantcells. (-)-Cryptanoside A (1) also inhibited Na+/K+-ATPase activity and increased the expressionof Akt and the p65 subunit of NF-& kappa;B but did not show any effectson the expression of PI3K. A molecular docking profile showed that(-)-cryptanoside A (1) binds to Na+/K+-ATPase, and thus 1 may directly targetNa(+)/K+-ATPase to mediate its cancer cell cytotoxicity.

Automated summary

A cardiac glycoside epoxide, (-)-cryptanoside A (1), was isolated from Cryptolepis dubia and showed potent cytotoxicity against various human cancer cell lines. It also inhibited Na+/K+-ATPase activity and increased the expression of Akt and the p65 subunit of NF-κB. Molecular docking analysis suggested that (-)-cryptanoside A (1) directly targets Na(+)/K+-ATPase to exhibit its cytotoxic effects on cancer cells.