Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells

Abstract

The saponin digitonin, the aglycone digitoxigenin and five cardiac glycosides were evaluated for cytotoxicity using primary cultures of tumor cells from patients and a human cell line panel (representing different cytotoxic drug-resistance patterns). Of these seven compounds, proscillaridin A was the most potent (IC(50): 6.4--76 nM), followed by digitoxin, and then ouabain, digoxin, lanatoside C, digitoxigenin and digitonin. Correlation analysis of the log IC(50) values for the cell lines in the panel showed that compound cytotoxicity was only slightly influenced by resistance mechanisms that involved P-glycoprotein, topoisomerase II, multidrug resistance-associated protein and glutathione-mediated drug resistance. Digitoxin and digoxin expressed selective toxicity against solid tumor cells from patients, while proscillaridin A expressed no selective toxicity against either solid or hematological tumor cells. The results revealed marked differences in cytotoxicity between the cardiac glycosides, both in potency and selectivity, and modes of action for cytotoxicity that differ from that of commonly used anticancer drugs.

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

“…In the latter, cardiac glycosides also inhibit testosterone production in vivo (38). Thus, while the cytotoxicity of some cardiac glycosides may correlate with Na ϩ ͞K ϩ -ATPase inhibition (18,21), the present study reveals a unique class of noncardioactive tumor-specific and potent cytotoxins, for which the mechanism of action remains to be elucidated.…”

“…The growing body of epidemiological (19,20), in vitro (18), and in vivo (31) evidence supporting the anticancer benefits of cardenolides has prompted the search for noncardioactive analogs that retain anticancer activity. The specific mechanism of cardenolide-induced cytotoxicity remains controversial.…”

“…In addition to its well known cardiac activity, which is mediated by inhibition of the plasma membrane Na ϩ ͞K ϩ -ATPase (17), digitoxin has demonstrated in vitro anticancer properties (18), and patient profiling suggests the survival rate of cancer patients taking digitoxin is statistically enhanced (19,20). Cardiac glycosides were also recently noted to inhibit the expression of four genes that are overexpressed in prostate cancer cells, including transcription factors and the apoptosis inhibitor survivin (21), and to provide protective effects against polyglutamine-based diseases (22).…”

“…Digitoxin also inhibits activation of the NF-B signaling pathway in cystic fibrosis (CF) cells, suppressing hypersecretion of IL-8, a protein implicated in lung inflammation, from CF lung epithelial cells (23). Given that the attached sugars are implicated as mediators of the unique spectrum of biological properties exhibited by cardiac glycosides (18,24), digitoxin provides an excellent model both to examine the general utility of neoglycosylation to efficiently construct a glycorandomized library and to directly assess the biological impact of varying the sugars attached to a given natural product-based drug.…”

Cardiac glycosides inhibit TNF-α/NF-κB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor

“…In addition, individual reports on oleandrin in TNF-␣-activated HeLa cells have shown that it can block activation of NF-B and activating protein 1 (4,5). Finally, digitoxin itself has been reported to have cytotoxic actions on certain types of human tumor cells in vitro (6,7). Thus, the action of cardiac glycosides on the NF-B pathway may have general implications beyond the specific application to blocking constitutive pathway activation in CF.…”