Inhibitory effect of the reversal agents V-104, GF120918 and Pluronic L61 on MDR1 Pgp-, MRP1- and MRP2-mediated transport

Abstract

The human multidrug transporter MDR1 P-glycoprotein and the multidrug resistance proteins MRP1 and MRP2 transport a range of cytotoxic drugs, resulting in multidrug resistance in tumour cells. To overcome this form of drug resistance in patients, several inhibitors (reversal agents) of these transporters have been isolated. Using polarized cell lines stably expressing human MDR1 , MRP1 or MRP2 cDNA, and 2008 ovarian carcinoma cells stably expressing MRP1 cDNA, we have investigated in this study the specificity of the reversal agents V-104 (a pipecolinate derivative), GF120918 (an acridone carboxamide derivative also known as GG918), and Pluronic L61 (a (poly)oxypropethylene and (poly)oxypropylene block copolymer). Transport experiments with cytotoxic drugs with polarized cell lines indicate that all three compounds efficiently inhibit MDR1 Pgp. Furthermore, V-104 partially inhibits daunorubicin transport by MRP1 but not vinblastine transport by MRP2. V-104 reverses etoposide resistance of 2008/MRP1 cells, whereas GF120918 does not reverse resistance due to MRP1. V-104 partially inhibits the export of the organic anion dinitrophenyl S -glutathione by MDCKII-MRP1 but not by MDCKII-MRP2 cells. Unexpectedly, export of the organic anion calcein by MDCKII-MRP1 and MDCKII-MRP2 cells is stimulated by Pluronic L61, probably because it relieves the block on entry of calcein AM into the cell by endogenous MDR1 Pgp. © 2000 Cancer Research Campaign

Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion

“…This provides additional support for the specific effects of the copolymer on the Pgp transport system. This conclusion is consistent with the recent studies by Evers et al (2000) and Batrakova et al (2001), demonstrating that Pluronic block copolymers (L61, P85) have pronounced effects, increasing accumulation and permeability of various Pgp-dependent drugs in MDR1-transfected cells, which overexpress Pgp. In addition to the effects on the Pgp efflux system, Pluronic block copolymer can affect other drug-resistant mechanisms present in MDR cells.…”

“…The data show that at lower concentrations of from 0.001-0.1%, P85 increases the accumulation of the probe in the cells. According to the previous studies, this effect is due to the inhibition of the Pgp efflux system Evers et al, 2000). At higher concentrations of P85 (0.1-5%) the R123 levels decrease.…”

Thyroid hormone export from cells: contribution of P-glycoprotein

“…JAR cells express minimal levels of P-gp (Mylona et al 1996, Atkinson et al 2003. In contrast, in the present study we used a polarized cell line, MDCKII-MDR derived from an MDCKII cell line, stably transfected with mdr1 (P-gp) cDNA (Evers et al 1997(Evers et al , 2000, and over-expressing P-gp (Borst et al 1999). We also used two novel and specific inhibitors of MDR transport, VX 853 and VX 710 as well as the less specific calcium channel blockers verapamil and nitrendipine which are conventionally used as inhibitors of P-gp.…”

“…We also used two novel and specific inhibitors of MDR transport, VX 853 and VX 710 as well as the less specific calcium channel blockers verapamil and nitrendipine which are conventionally used as inhibitors of P-gp. A similar approach has been successfully employed to examine interactions of P-gp and cytotoxics used clinically, in which an earlier generation P-gp reversal agent, V-104 (Vertex Pharmaceuticals), effectively inhibited daunorubicin and vinblastine transport in MDCKII-MDR cells (Evers et al 2000).…”

The Role of PDE-5 Inhibitors in Prostate Cancer

“…As a result, a number of compounds have been identified with the ability to inhibit individual or several transporters by blocking drug efflux, increasing drug accumulation and thus sensitizing resistant cancer cells. Several of these agents, including cyclosporine A, VX-710 (biricodar), Verapamil (Germann et al, 1997;Minderman et al, 2004;Qadir et al, 2005), LY475776 (Dantzig et al, 2004), V-104 and GF-120918 (elacridar) (Evers et al, 2000) can inhibit/suppresses the function of multiple transporters including ABCB1, ABCC1, and ABCG2. Unfortunately, most of these inhibitors have not been translated into clinical trials due to unfavorable side effects, toxic pharmacokinetic interactions, or simply because the magnitude of improvement in therapeutic outcome of these inhibitors with conventional chemotherapeutic agents is either nonsignificant or inconclusive (Szakacs et al, 2006).…”