Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918

This study was aimed at characterizing the role of BCRP/MXR/ABCP (BCRP) in resistance of the human ovarian tumor cell lines T8 and MX3 to camptothecin s more extensively and investigating whether resistance can be reversed by inhibiting BCRP by GF120918. Camptothecins studied were topotecan, CPT-11, and its active metabolite SN-38, 9-aminocamptothecin, and the novel experim ental camptothecins NX211, DX8951f, and BNP1350. Notably, DX8951f and BNP13 50 appeared to be very poor substrates for BCRP, with much lower resistance factors observed both in Tg and MX3 cells than observed for the other camp tothecins tested. In the presence of a nontoxic dose level of GF120918, the intracellular accumulation of topotecan in the T8 and MX3 cells was comple tely restored to the intracellular levels observed in the sensitive IGROV1 parental cell line, This resulted in almost complete reversal of drug resis tance to topotecan and to most of the other topoisomerase I drugs tested in the TS cell line and to complete reversal in the MX3 cells, However, coinc ubation of DX8951f or BNP1350 with GP120918 did not affect the cytotoxicity of either of these drugs significantly, From the combined data, we conclud e that the affinities of topoisomerase I drugs for BCRP are, in decreasing order: SN-38 > topotecan > 9-aminocamptothecin similar to CPT-11 > NX211 > DX8951f > BRTP1350. Furthermore, GF120918 appears to be a potent reversal a gent of BCRP-mediated resistance to camptothecins, with almost complete rev ersal noted at 100 nM. Potential BCRP-mediated resistance to topoisomerase I inhibitors can also be avoided by using the BCRP-insensitive drugs DX8951 f or BNP1350. This observation may have important clinical implications for future development of novel camptothecins.