NR ADQF
AU Dubowchik,G.M.; Padilla,L.; Edinger,K.; Firestone,R.A.
TI Reversal of doxorubicin resistance and catalytic neutralization of lysosomes by a lipophilic imidazole
QU Biochimica et Biophysica Acta 1994 Apr 20; 1191(1): 103-8
PT journal article
AB 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.
MH Catalysis; Cells, Cultured; Doxorubicin/metabolism/*pharmacology; Drug Resistance; Human; Hydrogen-Ion Concentration; Imidazoles/*pharmacology; Lysosomes/chemistry/*drug effects; Tumor Cells, Cultured; Verapamil/pharmacology
AD Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492-7660.
SP englisch
PO Niederlande