Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer.

Here, we showed the antibiotic salinomycin (SAL) combined with GEF exerted synergistic cytotoxicity effects in colorectal cancer cells irrespective of their EGFR and KRAS status, with a relatively low toxicity to normal cells. Additionally, combination of the two drugs overcame Ras-induced resistance and the acquired resistance to GEF. Further, we identified a new potential mechanism of this cooperative interaction by showing that GEF and SAL acted together to enhance production of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP) and lysosomal membrane potential (LMP).