| | |  | | | | Record from Web of Science® | | | | | | |
| Defective acidification in human breast tumor cells and implications for chemotherapy |
|
|
| Author(s): Altan N, Chen Y, Schindler M, Simon SM |
| Source: JOURNAL OF EXPERIMENTAL MEDICINE Volume: 187 Issue: 10 Pages: 1583-1598 Published: MAY 18 1998 |
| Times Cited: 130 References: 76 |
| Abstract: 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 ex eluded 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 Al, 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Simon, SM (reprint author), Rockefeller Univ, Lab Cellular Biophys, 1230 York Ave,Box 304, New York, NY 10021 USA |
Addresses:
1. Rockefeller Univ, Lab Cellular Biophys, New York, NY 10021 USA
2. Michigan State Univ, Dept Biochem, E Lansing, MI 48824 USA |
| Publisher: ROCKEFELLER UNIV PRESS, 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA |
| Subject Category: Immunology; Medicine, Research & Experimental |
| IDS Number: ZP559 |
| ISSN: 0022-1007 |
|
| | | | | | | | | Record from Web of Science® | | | | | | | | | |