Breast cancer resistance protein directly confers SN-38 resistance of lungcancer cells

Breast cancer resistance protein (BCRP), an ABC half-transporter, is overex pressed in cancer cell lines selected with doxorubicin/verapamil, topotecan , or mitoxantrone. BCRP-overexpressing cells show cross-resistance to campt othecin derivatives such as irinotecan, SN-38 (the active metabolite of iri notecan), and topotecan. To test whether BCRP confers SN-38 resistance, we selected two SN-38 resistant sublines from PC-6 human small-cell lung cance r cells by SN-38, and then characterized these cells. Compared to PC-6 cell s, the resistant sublines PC-6/SN2-5 and PC-6/SN2-5H were approximately 18- and 34-fold resistant, respectively. The intracellular SN-38 accumulation was reduced in the sublines, and BCRP mRNA was overexpressed in proportion to the degree of SN-38 resistance. These findings suggest that BCRP confers SN-38 resistance in the sublines. To confirm this hypothesis, PC-6/SN2-5 c ells were transfected with antisense oligonucleotides complementary to port ions of BCRP mRNA. The antisense oligonucleotides significantly suppressed BCRP mRNA expression, and enhanced SN-38 sensitivity in the subline. These data indicate that BCRP is directly involved with SN-38 resistance, by effl ux transport of SN-38. (C) 2001 Academic Press.