Lysosomal accumulation of drugs in drug-sensitive MES-SA but not multidrug-resistant MES-SA/Dx5 uterine sarcoma cells

Exing Wang, Michele D. Lee, Kenneth Dunn

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Sequestration of drugs in intracellular vesicles has been associated with multidrug-resistance (MDR), but it is not clear why vesicular drug accumulation, which depends upon intracellular pH gradients, should be associated with MDR. Using a human uterine sarcoma cell line (MES-SA) and a doxorubicin (DOX)-resistant variant cell line (Dx-5), which expresses p- glycoprotein (PGP), we have addressed the relationship between multidrug resistance, vesicular acidification, and vesicular drug accumulation. Consistent with a pH-dependent mechanism of vesicular drug accumulation, studies of living cells vitally labeled with multiple probes indicate that DOX and daunorubicin (DNR) predominately accumulate in lysosomes, whose lumenal pH was measured at < 4.5, but are not detected in endosomes, whose pH was measured at 5.9. However, vesicular DOX accumulation is more pronounced in the drug-sensitive MES-SA cells and minimal in Dx5 cells even when cellular levels of DOX are increased by verapamil treatment. While lysosomal accumulation of DOX correlated well with pharmacologically induced differences in lysosome pH in MES-SA cells, lysosomal accumulation was minimal in Dx5 cells regardless of lysosomal pH. We found no differences in the pH of either endosomes or lysosomes between MES-SA and Dx5 cells, suggesting that, in contrast to other MDR cell systems, the drug-resistant Dx5 cells are refractory to pH-dependent vesicular drug accumulation. These studies demonstrate that altered endomembrane pH regulation is not a necessary consequence of cell transformation, and that vesicular sequestration of drugs is not a necessary characteristic of MDR. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)263-274
Number of pages12
JournalJournal of Cellular Physiology
Volume184
Issue number2
DOIs
StatePublished - 2000

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Sarcoma
Multiple Drug Resistance
Doxorubicin
Pharmaceutical Preparations
Lysosomes
Cells
Endosomes
Daunorubicin
Acidification
Cell Line
Proton-Motive Force
Verapamil
Refractory materials
Glycoproteins

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Lysosomal accumulation of drugs in drug-sensitive MES-SA but not multidrug-resistant MES-SA/Dx5 uterine sarcoma cells. / Wang, Exing; Lee, Michele D.; Dunn, Kenneth.

In: Journal of Cellular Physiology, Vol. 184, No. 2, 2000, p. 263-274.

Research output: Contribution to journalArticle

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