Chemotherapeutic activity of ellagic acid combined with doxorubicin nanoliposomes in 4T1 breast cancer cells andNIH3T3 normal breast fibroblast cells

Nowadays, there is an increasing emphasis on combination chemotherapy using cytotoxic andnaturally occurring chemopreventive agents, having different mechanisms of action with nonoverlappingtoxicity. The fruit of the Punica granatum (pomegranate) contains a lot of phytochemicalswith antioxidant properties, thought to be due to the action of ellagic acid (ELG), the main polyphenolin pomegranate. ELG is also seen at high concentrations in grapes and many berries includingstrawberries, raspberries and cranberries. Some studies reported that it can induce G1 cell cycle arrest,induction of apoptosis and inhibition of overall tumor cells growth.In the present study we investigated the cytotoxic effects of combined Doxil, nanoliposomaldoxorubicin (DXL), and ELG on 4T1 breast cancer cells compared with NIH3T3 normal mousefibroblast cells. The results showed that the cytotoxic effects of ELG on viability of 4T1 cancer cellswere higher than NIH3T3 normal cells (IC50 6.15 ± 0.96 nm/ml for 4T1 cancer cells compared with148.92 ± 34.85 nm/ml for NIH3T3 normal cells, respectively). Furthermore, the results showed thatdepending on the molar ratio of ELG to DXL in combination therapy, the effect of ELG ontherapeutic efficacy of DXL could be synergistic, additive or antagonistic in both 4T1 cancer cells andNIH3T3 normal cells. In conclusion, these findings confirm that ELG, as an antiproliferative agentcan increase the chemotherapeutic efficacy of DXL in 4T1 cancer cells.