title: Combination of suboptimal doses of inhibitors targeting different domains of LtrMDR1 efficiently overcomes resistance of Leishmania spp. to Miltefosine by inhibiting drug efflux.
abstract: 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-beta-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.
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Pérez-Victoria
authors.forename: Fernando
authors.initials: F
authors.lastname: Cortés-Selva
authors.forename: Adriana
authors.initials: A
authors.lastname: Parodi-Talice
authors.forename: Boris I
authors.initials: BI
authors.lastname: Bavchvarov
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Pérez-Victoria
authors.forename: Francisco
authors.initials: F
authors.lastname: Muñoz-Martínez
authors.forename: Mathias
authors.initials: M
authors.lastname: Maitrejean
authors.forename: M Paola
authors.initials: MP
authors.lastname: Costi
authors.forename: Denis
authors.initials: D
authors.lastname: Barron
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000378:metabolism; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004351:Drug Resistance; D006801:Humans; D007891:Leishmania / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D003986:Dibenzocycloheptenes; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D010767:Phosphorylcholine; C039128:miltefosine; C095179:zosuquidar trihydrochloride; C083501:Elacridar