Inhibition of cell proliferation, invasion and migration by the cardenolides digitoxigenin monodigitoxoside and convallatoxin in human lung cancer cell line

Abstract

Cardiac glycosides consist of a large family of naturally derived compounds that are clinically used to treat congestive heart failure, and also present anticancer properties. In this study, the cytotoxic effects of two cardenolides, digitoxigenin monodigitoxoside (DGX) and convallatoxin (CON) were screened in four human tumour cell lines. Both compounds showed anti-proliferative effects in all tumour cells, at nanomolar concentrations. Since the human lung cancer cell line A549 was the most sensitive, we investigated the anti-proliferative, anti-migratory and anti-invasive effects of these cardenolides. DGX and CON reduced A549 cell migration, being able to reduce more than 90% of cell invasion. Their effects on the expression of key regulators of metastatic mechanism showed decreased levels of MMP-2, MMP-9 and p-FAK. Both compounds also presented low toxicity for healthy cells. Finally, this work provides the first insights into the effects of these cardenolides on key steps of lung cancer metastasis.

Anti‐Tumor Effects of Cardiac Glycosides on Human Lung Cancer Cells and Lung Tumorspheres

“…2A and 3B,C). Similar to Digitoxigenin, another cardiac glycoside that lack the sugar moiety (Schneider et al, 2015;Zhang et al, 2015), ST was a weak inhibitor of Fig. 4.…”

“…proliferation when compared to CT or PS (Schneider et al, 2015). On the other hand, CT and PS that contain one sugar residue were much stronger inhibitors, suggesting that sugar moiety is important for conferring anti-cancer activity.…”

“…). The inhibitory effects on invasion and migration CT and two other cardiac glycosides (digitoxigenin and monodigitoxoside) was recently demonstrated on the A549 human lung cancer cell line (Schneider et al, ) clearly indicating that this class of anti‐cancer drugs have a great potential for targeting lung cancer cells. Both CT and PS also down regulated the expression of proteins associated with the EMT phenotype (Fig.…”

“…2A and 3B,C). Similar to Digitoxigenin, another cardiac glycoside that lack the sugar moiety (Schneider et al, ; Zhang et al, ), ST was a weak inhibitor of proliferation when compared to CT or PS (Schneider et al, ). On the other hand, CT and PS that contain one sugar residue were much stronger inhibitors, suggesting that sugar moiety is important for conferring anti‐cancer activity.…”

“…CT is also isolated from the trunk bark of Antiaris toxicaria (Levrier et al, 2012). Regardless of the source, CT exerts cytotoxic effects on a number of cancer cell lines (Felth et al, 2009;Levrier et al, 2012;Yang et al, 2014;Schneider et al, 2015) but its effects in cancer-stem like cells is not known. In humans, the serum concentration of CT required to produce symptoms is unknown but in animal models the toxic levels of CT has been reported to be in the range of 18-180 mM (Fink et al, 2014).…”