Cetuximab and epirubicin HCl-combined application as a possibility to treat both parental and epirubicin HCl-resistant liver cancer cells.

Abstract

Targeted chemotherapeutics such as cetuximab can cause many side effects such as skin toxicity when used in high concentrations. In addition, cancer cells can develop resistance to some of the anticancer agents during treatment. The lack of the desired success in chemotherapy and the development of resistance to chemotherapeutics, such as epirubicin HCl, suggest that there is a need for combined therapies. The combination of targeted chemotherapeutics and conventional chemotherapy drugs may lead to the emergence of new strategies in the treatment of cancer. In this study, cytotoxic, antiproliferative, cell cycle inhibitive, oxidative stress generation, and apoptotic effects and effect mechanisms of cetuximab alone and together with epirubicin HCl on parental liver cancer cells (P-Hep G2) and epirubicin HCl-resistant liver cancer cells (R-Hep G2) were investigated. Cytotoxic effects of cetuximab alone and with epirubicin-HCl on cells were determined by Cell Titer-Blue® Cell Viability and Lactate Dehydrogenase Activity tests. Cell cycle distributions and apoptosis were detected by reverse transcription polymerase chain reaction (RT-PCR). Cetuximab with epirubicin HCl treatment increased the cytotoxic effect on both cells. Caspase-3/7 activity increased 3 and 1.5 times in comparison with control group in P-Hep G2 and R-Hep G2 cells, respectively, after treating with cetuximab alone, whereas the increase was found to be approximately 4.7 and 2.5 times when cetuximab was treated with epirubicin HCl in P-Hep G2 and R-Hep G2 cells, respectively. Both cetuximab alone and together with epirubicin HCl treatments caused increases in Bax/Bcl-2 ratio in both cells. Treatment of cetuximab with epirubicin HCl to P-Hep G2 and R-Hep G2 cells was found to be more effective in cytotoxic effect and inducing apoptosis comparison to cetuximab alone treatment. In addition, combination treatment showed different effects on pro-apoptotic/anti-apoptotic genes expression according to cells drug resistance properties.