title: pH and drug resistance. II. Turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs.
abstract: Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with cancer. The primary mechanism leading to a multidrug-resistant phenotype is assumed to be plasma-membrane localized overexpression of drug efflux transporters, such as P-glycoprotein (P-gp). However, acidic intracellular organelles can also participate in resistance to chemotherapeutic drugs. In this study, we investigated, both experimentally and theoretically, the effect of acidic vesicle turnover on drug resistance. We have developed a general model to account for multiple mechanisms of resistance to weakly basic organic cations, e.g. anthracyclines and Vinca alkaloids. The model predicts that lower cytosolic concentrations of drugs can be achieved through a combination of high endosomal turnover rates, a low endosomal pH, and an alkaline-inside pH gradient between cytosol and the extracellular fluid. Measured values for these parameters have been inserted into the model. Computations using conservative values of all parameters indicate that turnover of acidic vesicles can be an important contributor to the drug-resistant phenotype, especially if vesicles contain an active uptake system, such as H+/cation exchange. Even conservative estimates of organic cation-proton antiport activity would be sufficient to make endosomal drug extrusion a potent mechanism of resistance to weakly basic drugs. The effectiveness of such a drug export mechanism would be comparable to drug extrusion via drug pumps such as P-gp. Thus, turnover of acidic vesicles can be an important factor in chemoresistance, especially in cells that do not overexpress plasma membrane-bound drug pumps like P-glycoprotein.
authors.affiliation: Department of Biochemistry, University of Arizona Health Sciences Center, Tucson 85724-5042, USA.
authors.forename: N
authors.initials: N
authors.lastname: Raghunand
authors.forename: R
authors.initials: R
authors.lastname: Martínez-Zaguilán
authors.forename: S H
authors.initials: SH
authors.lastname: Wright
authors.forename: R J
authors.initials: RJ
authors.lastname: Gillies
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D019342:Acetic Acid / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000502:physiology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D011992:Endosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017136:Ion Transport; D008564:Membrane Potentials; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D015388:Organelles / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases; D019342:Acetic Acid