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J. Exp. Med.,
Volume 187, Number 10, May 18, 1998 1583-1598
By
From the * Laboratory of Cellular Biophysics, Rockefeller University, New York 10021; and the 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.
Department of Biochemistry, Michigan State University, East Lansing, Michigan 48824
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