Novel tetrahydroisoquinolin-ethyl-phenylamine based multidrug resistance inhibitors with broad-spectrum modulating properties
Abstract
The ATP-binding cassette transporters P-glycoprotein (Pgp) and BCRP are implicated in multidrug resistance (MDR) of many tumors. Multi-targeted inhibitors such as cyclosporin A, have been shown to circumvent MDR in clinical trials. Here, we present the characterization of a novel class of effective and multi-targeted tetrahydroisoquinolin-ethyl-phenylamine based MDR inhibitors. The novel MDR inhibitors, XR9577, WK-X-34, WK-X-50 and WK-X-84 were examined for cellular toxicity in several cell lines. Chemosensitivity and inhibition of BCRP-mediated mitoxantrone efflux were analyzed in BCRP-overexpressing MCF7/mx cells. Chemosensitivity towards daunorubicin and inhibition of Pgp-mediated efflux of (99m)Tc-Sestamibi were examined in Pgp-overexpressing A2780/Adr cells. Potential MRP-interactions were evaluated with 5-CFDA efflux assays in selectively transfected MRP-1, -2 and -3 cell lines. All WK-X-compounds showed significant BCRP inhibition in the MCF7/mx cells resulting in significant increases in mitoxantrone intracellular accumulation and 200-300 fold increases in mitroxantrone cytotoxicity. WK-X-34 and XR9577 were also potent inhibitors of Pgp, increasing (99m)Tc-Sestamibi accumulation with IC(50) values in the nM range. Dauno...Continue Reading
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Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.