pH and drug resistance. II. turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs

• Published in: Biochemical pharmacology Vol. 57; no. 9; pp. 1047 - 1058
• Main Authors: Raghunand, Natarajan, Martı́nez–Zaguilán, Raul, Wright, Stephen H, Gillies, Robert J
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-05-1999; Elsevier Science
• Subjects: Acetic Acid - metabolism; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biological and medical sciences; Cell Membrane - physiology; compartmentation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Endosomes - metabolism; exocytosis; Female; General aspects; Humans; Hydrogen-Ion Concentration; Ion Transport; mathematical model; Medical sciences; Membrane Potentials; Mice; Mice, SCID; Models, Biological; multidrug resistance; Organelles - metabolism; organic cation transport; Pharmacology. Drug treatments; Proton-Translocating ATPases - metabolism; Tumor Cells, Cultured; Vacuolar Proton-Translocating ATPases; vacuolar-type H +-ATPase; mathematical model; multidrug resistance; compartmentation; exocytosis; vacuolar-type H +-ATPase; organic cation transport; Antineoplastic agent; Human; Vesicle; Organic cation; Enzyme; Biological transport; Rodentia; P Glycoprotein; H; Ion transport; transporting ATP synthase; Exocytosis; Cytosol; Vertebrata; Mammalia; Mouse; Animal; Multiple resistance; pH; Hydrolases; Mathematical model; Tumor cell
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(99)00021-0

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.