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PMID: 9584137 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Defective acidification in human breast tumor cells and implications for chemotherapy.

The Journal of experimental medicine ·Vol. 187 ·No. 10 ·1998-05-18 ·Pages 1583-98

Altan N, Chen Y, Schindler M, Simon SM

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 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.

MeSH Terms
Anti-Bacterial Agents/pharmacology Antibiotics, Antineoplastic/pharmacology,therapeutic use Antineoplastic Agents/pharmacology,therapeutic use Breast Neoplasms/drug therapy,genetics,metabolism,pathology Cell Compartmentation Doxorubicin/pharmacology,therapeutic use Drug Resistance, Multiple Female Humans Hydrogen-Ion Concentration Ionophores/pharmacology Macrolides Monensin/pharmacology Tumor Cells, Cultured
Chemicals
Anti-Bacterial Agents Antibiotics, Antineoplastic Antineoplastic Agents Ionophores Macrolides Doxorubicin concanamycin A bafilomycin A1 Monensin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Altan N
Laboratory of Cellular Biophysics, Rockefeller University, New York 10021, USA.
Chen Y
Schindler M
Simon S M
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.187.10.1583
Published
1998-05-18
Pages
1583-98
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2212293
Subset
IM
Grants
NIGMS NIH HHS · GM-07739 · United States
External Links
PubMed source DOI: 10.1084/jem.187.10.1583 PMC Full Text View journal details
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