Tamoxifen inhibits acidification in cells independent of the estrogen receptor.
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.
Altan
N
N
Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Chen
Y
Y
Schindler
M
M
Simon
S M
SM
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001692:Biological Transport; D001896:Boron Compounds; D001943:Breast Neoplasms; D003593:Cytoplasm / Q000502:physiology; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity; D019008:Drug Resistance, Neoplasm; D011992:Endosomes / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000187:drug effects / Q000502:physiology*; D018942:Macrolides; D008985:Monensin / Q000494:pharmacology*; D009447:Neuroblastoma; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology*; D014168:Transferrin / Q000378:metabolism; D014407:Tumor Cells, Cultured
C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D000900:Anti-Bacterial Agents; D001896:Boron Compounds; D005456:Fluorescent Dyes; D018942:Macrolides; D011960:Receptors, Estrogen; D014168:Transferrin; D013629:Tamoxifen; D004317:Doxorubicin; C040929:bafilomycin A1; D008985:Monensin