NSC23925, Identified in a High-Throughput Cell-Based Screen, Reverses Multidrug Resistance

摘要: Author(s): Duan, Zhenfeng; Choy, Edwin; Hornicek, Francis J | Abstract: BackgroundMultidrug resistance (MDR) is a major factor which contributes to the failure of cancer chemotherapy, and numerous efforts have been attempted overcome MDR. To date, none these attempts yielded tolerable effective therapy reverse MDR; thus, identification new agents would be useful both clinically scientifically.Methodology/principal findingsTo identify small molecule compounds that can chemoresistance, we developed 96-well plate high-throughput cell-based screening assay in paclitaxel resistant ovarian cell line. Coincubating cells with sublethal concentration combination each 2,000 from National Cancer Institute Diversity Set Library, identified previously uncharacterized molecule, NSC23925, inhibits Pgp1 reverses MDR1 (Pgp1) but does not inhibit MRP or BCRP-mediated The cytotoxic activity NSC23925 was further evaluated using panel lines expressing Pgp1, MRP, BCRP. We found at g10 microM moderately proliferation sensitive almost equal activity, its inhibitory effect altered by co-incubation inhibitor, verapamil, suggesting itself substrate Pgp1. Additionally, increases intracellular accumulation substrates: calcein AM, Rhodamine-123, paclitaxel, mitoxantrone, doxorubicin. Interestingly, observed that, although directly function dose-dependent manner without altering total expression level actually stimulates ATPase Pgp, phenomenon seen other Pgp inhibitors.Conclusions/significanceThe ability restore sensitivity effects chemotherapy prevent could significantly benefit patients.