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PMID: 10200279 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Tamoxifen inhibits acidification in cells independent of the estrogen receptor.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 8 ·1999-04-13 ·Pages 4432-7

Altan N, Chen Y, Schindler M, Simon SM

Abstract

Tamoxifen has been reported to have numerous physiological effects that are independent of the estrogen receptor, including sensitization of resistant tumor cells to many chemotherapeutic agents. Drug-resistant cells sequester weak base chemotherapeutics in acidic organelles away from their sites of action in the cytosol and nucleus. This work reports that tamoxifen causes redistribution of weak base chemotherapeutics from acidic organelles to the nucleus in drug-resistant cells. Agents that disrupt organelle acidification (e.g., monensin, bafilomycin A1) cause a similar redistribution. Measurement of cellular pH in several cell lines reveals that tamoxifen inhibits acidification of endosomes and lysosomes without affecting cytoplasmic pH. Similar to monensin, tamoxifen decreased the rate of vesicular transport though the recycling and secretory pathways. Organellar acidification is required for many cellular functions, and its disruption could account for many of the side effects of tamoxifen.

MeSH Terms
Anti-Bacterial Agents/pharmacology Biological Transport Boron Compounds Breast Neoplasms Cytoplasm/physiology Doxorubicin/pharmacokinetics,toxicity Drug Resistance, Neoplasm Endosomes/drug effects,physiology Female Fluorescent Dyes Humans Hydrogen-Ion Concentration Lysosomes/drug effects,physiology Macrolides Monensin/pharmacology Neuroblastoma Receptors, Estrogen/drug effects,physiology Tamoxifen/pharmacology Transferrin/metabolism Tumor Cells, Cultured
Chemicals
4,4-difluoro-4-bora-3a,4a-diaza-s-indacene Anti-Bacterial Agents Boron Compounds Fluorescent Dyes Macrolides Receptors, Estrogen Transferrin Tamoxifen Doxorubicin bafilomycin A1 Monensin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Altan N
Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Chen Y
Schindler M
Simon S M
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.8.4432
Published
1999-04-13
Pages
4432-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC16349
Subset
IM
Grants
NIGMS NIH HHS · T32 GM007739 · United States
NIGMS NIH HHS · GM07739 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.8.4432 PMC Full Text View journal details
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