Cetuximab enhances the efficiency of irinotecan through simultaneously inhibiting the MAPK signaling and ABCG2 in colorectal cancer cells

Abstract

Background: The present study sought to investigate the combined effects of cetuximab and irinotecan on colorectal cancer cells as well as the mechanisms underlying their anti-cancer effects.

Material and methods: High performance liquid chromatography, Hoechst staining assay, and western blotting analysis were used to detect intracellular drug concentrations, cell apoptosis, and protein expression in the presence of cetuximab, irinotecan, and the combination of both.

Results: Cetuximab was found to increase intracellular concentrations of irinotecan as well as cytotoxicity by inhibiting the epidermal growth factor receptor and, by extension, the downstream RAS-RAF-MEK-ERK signaling pathway. Cetuximab therefore induced apoptosis and improved the effect of irinotecan in colorectal cancer cells. It was also shown that cetuximab inhibited the drug efflux activity of ABCG2. In combination with irinotecan, cetuximab can both significantly induce cell apoptosis by inhibiting the RAS-RAF-MEK-ERK signaling pathway and improve the effects of irinotecan by decreasing drug efflux through the inhibition of ABCG2.

Conclusion: These features contribute to its anti-cancer potential.

Keywords: ABCG2; Apoptosis; Cetuximab; Colorectal cancer; Drug efflux; Irinotecan.