P-glycoprotein (P-gp, multidrug resistance 1 (MDR1)) overexpression confers multidrug resistance to cancer cells, and P-gp in cell lines transfected with MDR1 or selected with chemotherapeutics significantly affect the anticancer drug efficacy. Although human cancer cell line panels consisting of defined tumor cell lines expressing endogenous P-gp have been used to screen drugs in pharmaceutical industries, endogenous P-gp affecting in vitro anticancer drug efficacy is unclear. The impact of P-gp expression on anticancer drug efficacy was assessed by using five colon cancer cell lines expressing varying endogenous P-gp levels and by selecting from the Cancer Cell Line Encyclopedia (CCLE). mRNA expression of MDR1 was considered as a surrogate of the protein expression of its gene product, P-gp, in CL-11, C2BBe1 and RKO cells, whereas P-gp protein expression in plasma membranes or crude membrane fractions was lower than expected from mRNA expression in CW-2 and CL-40 cells. The EC50 of paclitaxel and vinorelbine decreased in the presence of a P-gp inhibitor in CW-2 and CL-11 cells that highly express P-gp. No significant alterations in EC50 were observed in the CL-40, C2BBe1 and RKO cells, which show lower P-gp expression. Accordingly, the apparent in vitro efficacy of anticancer drugs could be underestimated if the endogenous P-gp expression is higher than in CL-11 cells. The effect of P-gp needs to be carefully evaluated in cell lines that highly express P-gp, which account for 1.5% of cancer cell lines, including all cancer types, and 14.5% of colon cancer cell lines in CCLE, considering the protein expression levels in plasma membranes.
Keywords: P-glycoprotein (P-gp); anticancer agents; drug development; drug efficacy; pharmacokinetics.
© 2018 John Wiley & Sons, Ltd.