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Articles

Nihal Altan^*, Yu Chen^*, Melvin Schindler, and Sanford M. Simon^*

From the ^* Laboratory of Cellular Biophysics, Rockefeller University, New York 10021; and the Department of Biochemistry, Michigan State University, East Lansing, Michigan 48824

Multidrug resistance (MDR) is a significant problem in the treatment of cancer. Chemotherapeutic drugs distribute through the cyto- and nucleoplasm of drug-sensitive cells but are excluded from the nucleus in drug-resistant cells, concentrating in cytoplasmic organelles. Weak base chemotherapeutic drugs (e.g., anthracyclines and vinca alkaloids) should concentrate in acidic organelles. This report presents a quantification of the pH for identified compartments of the MCF-7 human breast tumor cell line and demonstrates that (a) the chemotherapeutic Adriamycin concentrates in acidified organelles of drug-resistant but not drug-sensitive cells; (b) the lysosomes and recycling endosomes are not acidified in drug-sensitive cells; (c) the cytosol of drug-sensitive cells is 0.4 pH units more acidic than the cytosol of resistant cells; and (d) disrupting the acidification of the organelles of resistant cells with monensin, bafilomycin A1, or concanamycin A is sufficient to change the Adriamycin distribution to that found in drug-sensitive cells, rendering the cell vulnerable once again to chemotherapy. These results suggest that acidification of organelles is causally related to drug resistance and is consistent with the hypothesis that sequestration of drugs in acidic organelles and subsequent extrusion from the cell through the secretory pathways contribute to chemotherapeutic resistance.

Key Words: multidrug resistance • pH • secretion • chemotherapy • breast cancer

N. Altan would like to thank the Merinoff Foundation, M. Schindler the Pardee Foundation (Midland, MI), and S.M. Simon the Keck Foundation, the Wolfensohn Foundation, the William and Helen Mazer Foundation, and the Irving A. Hansen Memorial Foundation for their financial support. Y. Chen was supported by National Institutes of Health grant MSTP GM-07739.

Abbreviations used: LAMP, lysosome-associated membrane protein; MDR, multidrug resistance; MRP, MDR-associated protein; Pgp, P-glycoprotein; PSS, protonation, sequestration, and secretion; SNARF, seminaphthorhodafluor; TGN, trans-Golgi network.

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