Reversal of multidrug resistance by verapamil analogues

Pereira, Elene; Teodori, Elisabetta; Dei, Silvia; Gualtieri, Fulvio; Garnier‐Suillerot, Arlette

doi:10.1016/0006-2952(95)00174-x

Cited by 37 publications

(29 citation statements)

References 23 publications

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“…While chloroquine, mefloquine, quinine, and pyronaridine are weak P-gp substrates, they inhibit the efflux of other P-gp substrates (8,9,11,14). Although our experiments did not assess whether the present antimalarial drugs behave in the same way, our results suggest limited P-gp-mediated pyronaridine and naphthoquine efflux at low micromolar concentrations.…”

mentioning

confidence: 58%

Role of P Glycoprotein in Absorption of Novel Antimalarial Drugs

Crowe

Ilett

Karunajeewa

et al. 2006

Antimicrob Agents Chemother

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Bidirectional transport of four novel antimalarial compounds was determined using Caco-2 cell monolayers. P glycoprotein-mediated efflux was greatest for pyronaridine (5 to 20 M) and low for naphthoquine (5 M). With 20 M naphthoquine, net efflux was blocked, suggesting saturation of the transporter. Piperaquine and dihydroartemisinin were not transported by the system. Permeability glycoprotein (P-gp) ATP-dependent transporters influence the passage of many drugs across epithelial barriers in the intestine, brain, liver, and kidney (1) and may alter their pharmacokinetic and/or pharmacodynamic properties. Several antimalarial drugs are substrates and/or inhibitors of P-gp (9, 10, 15). In the intestine, P-gp has a secretory function which can contribute to low bioavailability and substrate-inhibitor interactions (14). The antimalarials dihydroartemisinin, naphthoquine, piperaquine, and pyronaridine are highly lipid soluble, with logP (log octanol-water partition coefficient) values of 2.6, 6.16, 6.16, and 4.98, respectively (ACD I Lab Software version 8.14 for Solaris; ACD Labs, Toronto, Canada). Evidence suggests that dihydroartemisinin and piperaquine have oral bioavailabilities of Ͻ50% (6, 7), while pyronaridine may interfere with P-gp-mediated transport (10, 11). We therefore investigated whether these four drugs are P-gp substrates and whether P-gp-mediated efflux explains the apparently low bioavailabilities of dihydroartemisinin and piperaquine.Drug transport was studied with an in vitro gastrointestinal model by using a monolayer of a CLEFF9 subclone of human Caco-2 cells with high P-gp-mediated efflux (4) and previously reported experimental protocols (3-5). Briefly, cells were seeded onto 0.6-cm 2 polycarbonate filters in 24-well plates and grown in high-glucose Dulbecco's modified Eagle's medium for 3 weeks. Following incubation in buffered Hanks balanced salt solution (HBSS) with or without specific efflux inhibitors for 30 min at 37°C, transepithelial electrical resistance was measured and assay medium/inhibitors were placed in the receiver chambers. Antimalarial drugs were added to the donor chamber of each well. The apical and basolateral chambers received 0.3 and 0.6 ml medium, respectively. Transepithelial electrical resistance measurements were repeated at the conclusion of the studies to ensure continued monolayer integrity.Naphthoquine was assayed using high-performance liquid chromatography (HPLC) with UV detection at 260 nm after separation through an Eclipse XDB-C 8 column (Agilent Technologies, Forest Hill, Australia) with a mobile phase of 22% acetonitrile, 10% methanol, and 68% 20 mM KH 2 PO 4 , with 11 mM triethylamine and 0.1% trifluoroacetic acid pumped at 1.2 ml/min. The limit of detection (LOD) was 30 nM. Pyronaridine was assayed by HPLC with detection at 277 nm after separation through a 100-by 4.6-mm (inside diameter), 3.5-m XTerra C 18 column (Waters Associates, Milford, MA), with acetonitrile buffer (80 mM KH 2 PO 4 , 22 mM triethylamine HCl, and 0.1% trifluoroacetic acid, pH 2....

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mentioning

confidence: 58%

Role of P Glycoprotein in Absorption of Novel Antimalarial Drugs

Crowe

Ilett

Karunajeewa

et al. 2006

Antimicrob Agents Chemother

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“…Methylation of this site imposes a certain rigidity on the molecule but the enantiomers are physically indistinguishable except for their optical activity (33,37). Nevertheless, Ro 44-5911 (the R-enantiomer) was substantially more effective (3-fold greater stimulation than observed with verapamil) than Ro 44-5912 (the S-enantiomer) which was similar to verapamil in its ability to stimulate GSH transport.…”

Section: Discussionmentioning

confidence: 98%

“…A large number of verapamil derivatives have been developed in an attempt to identify compounds that retain the resistance reversing activity of the parent compound without its adverse cardiovascular effects (32)(33)(34). We previously reported that one of these analogs, N- (3,4-dimethoxyphenethyl…”

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confidence: 99%

Structure–Activity Studies of Verapamil Analogs That Modulate Transport of Leukotriene C4 and Reduced Glutathione by Multidrug Resistance Protein MRP1

Loe

Oleschuk

Deeley

et al. 2000

Biochemical and Biophysical Research Communications

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“…We hope to decrease the effective concentration of each isomer, especially the S-isomer, to escape their cardiocytotoxic effects. Such verapamil analogs, which reverse the MDR phenotype induced by P-glycoprotein, were found by Pereira et al (31). Safety tests of iodinated derivatives will be performed on cardiomyocytes to determine whether iodination of the B-phenyl ring decreases toxicity.…”

Section: Discussionmentioning

confidence: 99%

(R)- and (S)-Verapamil Differentially Modulate the Multidrug-resistant Protein MRP1

Perrotton

Trompier

Chang

et al. 2007

Journal of Biological Chemistry

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The multidrug-resistant protein MRP1 (involved in the cancer cell multidrug resistance phenotype) has been found to be modulated by racemic verapamil (through stimulation of glutathione transport), inducing apoptosis of human MRP1 cDNA-transfected baby hamster kidney 21 (BHK-21) cells and not of control BHK-21 cells. In this study, we show that the two enantiomers of verapamil have different effects on MRP1 activity. Only the S-isomer (not the R-isomer) potently induced the death of MRP1-transfected BHK-21 cells. The decrease in cellular glutathione content induced by the S-isomer, which was not observed with the R-isomer, was stronger than that induced by the racemic mixture, indicating that the R-isomer antagonized the S-isomer effect. Both enantiomers altered leukotriene C 4 and calcein transport by MRP1. Thus, the R-isomer behaved as an inhibitor, which was confirmed by its ability to revert the multidrug resistance phenotype toward vincristine. Molecular studies on purified MRP1 using fluorescence spectroscopy showed that both enantiomers bound to MRP1 with high affinity, with the binding being prevented by glutathione. Furthermore, conformational changes induced by the two enantiomers (monitored by sodium iodide accessibility of MRP1 tryptophan residues) were quite different, correlating with their distinct effects. (S)-Verapamil induces the death of potentially resistant tumor cells, whereas (R)-verapamil sensitizes MRP1-overexpressing cells to chemotherapeutics. These results might be of great potential interest in the design of new compounds able to modulate MRP1 in chemotherapy.Resistance of tumors to multiple structurally unrelated anticancer drugs is one of the major obstacles to successful cancer chemotherapy. Failure to achieve complete and long-lasting responses is a common clinical problem that limits the curative potential of anticancer drugs in clinical oncology. Human multidrug resistance (MDR) 2 is frequently associated with the overexpression of three transporters belonging to the ATP-binding cassette (ABC) protein superfamily, P-glycoprotein (ABCB1), the multidrug-resistance protein MRP1 (ABCC1), and the breast cancer resistance protein (ABCG2) (1), which can actively extrude anticancer drugs from the cell at the expense of ATP hydrolysis. MRP1 transports organic anions, many of which are conjugated to GSH, sulfate, or glucuronate; physiological substrates of MRP1 include GSH and leukotriene C 4 (LTC 4 ) (2). Cytotoxic drugs in clinical use against cancer such as vincristine, vinblastine, and daunorubicin are cotransported with GSH (2). Although a number of modulators have been found (3), the mechanism of inhibition is poorly understood. In many cases, a competitive inhibition toward substrate was described, as for the leukotriene antagonist MK571, which is considered a reference inhibitor for MRP1 (4). Interesting but complex results have been obtained with two classes of modulators: flavonoids and verapamil. Dietary flavonoids such as apigenin have been shown to interact with MRP1 (5), ...

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Reversal of multidrug resistance by verapamil analogues

Cited by 37 publications

References 23 publications

Role of P Glycoprotein in Absorption of Novel Antimalarial Drugs

Role of P Glycoprotein in Absorption of Novel Antimalarial Drugs

Structure–Activity Studies of Verapamil Analogs That Modulate Transport of Leukotriene C4 and Reduced Glutathione by Multidrug Resistance Protein MRP1

(R)- and (S)-Verapamil Differentially Modulate the Multidrug-resistant Protein MRP1

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