Altered Drug Membrane Permeability in a Multidrug-Resistant Leishmania tropica Line

Chiquero, M J; Pérez‐Victoria, José M.; O’Valle, Francisco; González-Ros, José M.; Moral, Raimundo García del; Ferragut, José A.; Castanys, Santiago; Gamarro, Francisco

doi:10.1016/s0006-2952(97)00385-7

Cited by 73 publications

(93 citation statements)

References 32 publications

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“…Classical modulators of mammalian MDR phenotype, such as VER and Cyclosporin-A, can reverse drug resistance mediated by these transporters [31], although they are not effective with MDR in Leishmania [17,32]. We tested pSNBR/8 kb SmaI-B transfectants cells for PEN r at nontoxic concentrations of VER, and verified that PEN r was reverted when compared with transfected cells not treated with VER and/or LmFA1 wild-type cells (Table 1, gray line; Fig.…”

Section: Role Of Prp1 In Pen R and Cross-resistance Studiesmentioning

confidence: 85%

Functional genetic identification of PRP1, an ABC transporter superfamily member conferring pentamidine resistance in Leishmania major

Coelho¹,

Beverley

Cotrim³

2003

Molecular and Biochemical Parasitology

123

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Section: Role Of Prp1 In Pen R and Cross-resistance Studiesmentioning

confidence: 85%

Functional genetic identification of PRP1, an ABC transporter superfamily member conferring pentamidine resistance in Leishmania major

Coelho¹,

Beverley

Cotrim³

2003

Molecular and Biochemical Parasitology

123

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“…Western blot analysis of crude Leishmania extracts was performed as previously detailed (30), with the polyclonal antibody against LtrMDR1 previously described by Chiquero et al (5).…”

Section: Methodsmentioning

confidence: 99%

“…However, a first case of in vitro Leishmania miltefosine resistance has already been described in a multidrug-resistant (MDR) line (38) and resistance can be very easily developed experimentally by either drug selection pressure (42) or mutagenesis (33). Miltefosine resistance in Leishmania is mainly due to a defect in drug internalization (31) as a consequence of either the overexpression of a P-glycoprotein (Pgp)-like transporter (LtrMDR1) (38), a drug efflux pump implicated in the MDR phenotype (5,35), or to the malfunctioning of the recently discovered miltefosine transporter LdMT (33). Interestingly, LtrMDR1 inhibition sensitizes MDR parasites to miltefosine (38).…”

mentioning

confidence: 99%

Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

Pérez‐Victoria

Cortés-Selva

Parodi-Talice

et al. 2006

Antimicrob Agents Chemother

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Miltefosine (hexadecylphosphocholine) is the first orally active drug approved for the treatment of leishmaniasis. We have previously shown the involvement of LtrMDR1, a P-glycoprotein-like transporter belonging to the ATP-binding cassette superfamily, in miltefosine resistance in Leishmania. Here we show that overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites. Although LtrMDR1 modulation might be an efficient way to overcome this resistance, a main drawback associated with the use of P-glycoprotein inhibitors is related to their intrinsic toxicity. In order to diminish possible side effects, we have combined suboptimal doses of modulators targeting both the cytosolic and transmembrane domains of LtrMDR1. Preliminary structure-activity relationships have allowed us to design a new and potent flavonoid derivative with high affinity for the cytosolic nucleotide-binding domains. As modulators directed to the transmembrane domains, we have selected one of the most potent dihydro-␤-agarofuran sesquiterpenes described, and we have also studied the effects of two of the most promising, latest-developed modulators of human P-glycoprotein, zosuquidar (LY335979) and elacridar (GF120918). The results show that this combinatorial strategy efficiently overcomes P-glycoprotein-mediated parasite miltefosine resistance by increasing intracellular miltefosine accumulation without any side effect in the parental, sensitive, Leishmania line and in different mammalian cell lines.

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“…ATP-binding cassette (ABC) transporters have been found to be involved in Leishmania species in vitro selected for metal resistance (reviewed in reference 30). The multidrug resistance (MDR) phenotype due to P-glycoprotein (Pgp)-like transporters has been extensively characterized in cancer cells (1,13) and protozoan parasites (41), including Plasmodium (45) and Leishmania (4,5,17) spp. Pgp is an ATP-dependent pump that exports a wide range of drugs from the cell, decreasing their intracellular concentration and preventing their cytotoxic activity.…”

mentioning

confidence: 99%

“…These concentrations produce undesirable side effects. In addition, these classical modulators of drug efflux in cancer cells only poorly sensitize the MDR phenotype in Leishmania parasites (4,17,33). Thus, new classes of more specific, nontransported inhibitors of Pgp-like transporters with lower host toxicity need to be developed.…”

mentioning

confidence: 99%

High-Affinity Binding of Silybin Derivatives to the Nucleotide-Binding Domain of a Leishmania tropica P-Glycoprotein-Like Transporter and Chemosensitization of a Multidrug-Resistant Parasite to Daunomycin

Pérez‐Victoria

Pérez-Victoria

Conseil

et al. 2001

Antimicrob Agents Chemother

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In order to overcome the multidrug resistance mediated by P-glycoprotein-like transporters in Leishmania spp., we have studied the effects produced by derivatives of the flavanolignan silybin and related compounds lacking the monolignol unit on (i) the affinity of binding to a recombinant C-terminal nucleotide-binding domain of the L. tropica P-glycoprotein-like transporter and (ii) the sensitization to daunomycin on promastigote forms of a multidrug-resistant L. tropica line overexpressing the transporter. Oxidation of the flavanonol silybin to the corresponding flavonol dehydrosilybin, the presence of the monolignol unit, and the addition of a hydrophobic substituent such as dimethylallyl, especially at position 8 of ring A, considerably increased the binding affinity. The in vitro binding affinity of these compounds for the recombinant cytosolic domain correlated with their modulation of drug resistance phenotype. In particular, 8-(3,3-dimethylallyl)-dehydrosilybin effectively sensitized multidrug-resistant Leishmania spp. to daunomycin. The cytosolic domains are therefore attractive targets for the rational design of inhibitors against P-glycoprotein-like transporters.

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Altered Drug Membrane Permeability in a Multidrug-Resistant Leishmania tropica Line

Cited by 73 publications

References 32 publications

Functional genetic identification of PRP1, an ABC transporter superfamily member conferring pentamidine resistance in Leishmania major

Functional genetic identification of PRP1, an ABC transporter superfamily member conferring pentamidine resistance in Leishmania major

Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

High-Affinity Binding of Silybin Derivatives to the Nucleotide-Binding Domain of a Leishmania tropica P-Glycoprotein-Like Transporter and Chemosensitization of a Multidrug-Resistant Parasite to Daunomycin

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