title: Reversal of doxorubicin resistance and catalytic neutralization of lysosomes by a lipophilic imidazole.
abstract: A number of lipophilic nitrogenous bases, designed to act as membrane-active, catalytic proton transfer agents, were tested for their ability to neutralize the acidity of lysosomes, a model for other acidic intracellular vesicles involved in drug sorting. The most successful of these, an imidazole 1, caused a 1.7 unit rise in lysosomal pH of RAW cells at 100 microM, compared to a 0.2 and 1.4 unit rise for ammonium chloride at 100 microM and 10 mM, respectively. Compound 1 also exhibited potent reversal of doxorubicin (DOX) resistance in the HCT116-VM46 cell line by a factor of 14 over the sensitive strain, and superior to that of widely used verapamil (VRP) by a factor of 1.75 at 20 microM. It also has antiviral properties, and potential applications in other lysosome-related areas such as immunotoxin potentiation and the control of bacterial toxins, immune response, prion replication, malaria and intralysosomal microorganisms.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492-7660.
authors.forename: G M
authors.initials: GM
authors.lastname: Dubowchik
authors.forename: L
authors.initials: L
authors.lastname: Padilla
authors.forename: K
authors.initials: K
authors.lastname: Edinger
authors.forename: R A
authors.initials: RA
authors.lastname: Firestone
mesh_terms: D002384:Catalysis; D002478:Cells, Cultured; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology*; D008247:Lysosomes / Q000737:chemistry / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
chemical_list: D007093:Imidazoles; D004317:Doxorubicin; D014700:Verapamil