Inhibiting ABCG2 by Ko143 May Enhance the Efficacy of Irinotecan Treatment in Colon Cancer

Abstract

ABCG2 has been supposed as a promising target conferring multidrug resistance on cancer cells. However, ABCG2 studies in cancer had conflicting results. The aim of this study was to evaluate the effect of Ko143, an ABCG2 specific inhibitor, in the treatment of colon cancer with irinotecan (and its active metabolite SN38), a basic chemotherapeutic agent in colon cancer. The correlations between the ABCG2 protein expression with the effect of SN38 were confirmed in human colon cancer (HCT116) and liver metastatic (KOSA2) cell lines established from HCT116. Inhibiting ABCG2 function by Ko143 was increase SN38 sensitivity in both of cell lines, additionally, this effect was proportional to the concentration and exposure time of Ko143. Using xenografted tumor models with HCT116 cells, efficacy of combination Ko143 and irinotecan in tumor killing were shown significant increase compare with irinotecan alone treatment (P < .05). Moreover, coordination treatment with irinotecan and prolonged Ko143 extended time of tumor size doubled by arresting the cell cycle at the G0 phase which has been verified by immunostaning using an Ki-67 and p21 antibody. Finally, immunohistochemistry staining showed ABCG2 over-expression on membrane of colon cancer cells after irinotecan treatment, especially combined with Ko143. Altogether, our results suggested that combination therapy involving Ko143, an ABCG2 inhibitor, and irinotecan may improve the efficacy of colon cancer treatment. These promising results warrant further investigation in clinical trials.