Defective acidification in human breast tumor cells and implications for chemotherapy. Academic Article uri icon

Overview

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.

publication date

  • May 18, 1998

Research

keywords

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Breast Neoplasms
  • Doxorubicin
  • Drug Resistance, Multiple
  • Macrolides

Identity

PubMed Central ID

  • PMC2212293

Scopus Document Identifier

  • 0032543207

PubMed ID

  • 9584137

Additional Document Info

volume

  • 187

issue

  • 10