Antitumoral Effects of Digoxin in The Liver Cancer Cell Line is mediated through Induction of Apoptosis and Down Regulation of HIF-Α Expression

Based on epidemiological evidences, cardiac glycosides such as digoxin have been recently proposed as an anticancer drug. However, the outcomes are controversial and even application of digoxin as an anticancer agent is doubtful. Hence, in the present study, the anticancer properties of digoxin and its potential mechanisms have been investigated in a liver cancer cell line i.e. HepG2. hep G2 cell line was cultivated in RPMI-1640 with %15 FBS and 2µM digoxin for 6, 12, 24 and 48 hours. Apoptosis was detected in the cells treated with digoxin using in situ cell detection kit. Furthermore, the cells were stained by Giemsa to study the occurrence of senescence following administration of digoxin. Expression of HIF- α was determined by RT-PCR after the cells exposed to digoxin as well. Our findings revealed that digoxin induces apoptosis in a time dependent manner. A significant number of apoptotic cells were observed after 48hours exposure to digoxin (P<0.05). It seems that digoxin elicits senescence in hepG2 cell line in time dependent manner as well. Following digoxin treatment, down regulation of HIF1-α was considerably detected in the liver cancer cell line. Again, the result was prominent after 48hrs. Our findings strongly suggest that digoxin exerts its antitumor properties through inducing of apoptosis, cellular senescence and changing of HIF1- α gene profile. Due to cytotoxic effects of digoxin on the cells, it would be essential to determine the minimum toxicity dose and the drug mechanisms before its application in clinics for the patients.