title: Tamoxifen subcellular localization; observation of cell-specific cytotoxicity enhancement by inhibition of mitochondrial ETC complexes I and III.
abstract: Recently, a nongenomic cytotoxic component of the chemotherapeutic agent tamoxifen (TAM) has been identified that predominantly triggers mitochondrial events. The present study delineates the intracellular fate of TAM and studies its interaction with a spectrum of cell homeostasis modulators primarily relevant to mitochondria. The subcellular localization of TAM was assessed by confocal fluorescence microscopy. The effect of the modulators on TAM cytotoxicity was assessed by standard MTT assays. Our findings show that in estrogen receptor positive MCF7 breast adenocarcinoma cells and DU145 human prostate cancer cells, TAM largely accumulates in the mitochondria and endoplasmic reticulum, but not lysosomes. Our results further demonstrate that in MCF7, but not in DU145 cells, mitochondrial electron transport chain complex I and III inhibitors exacerbate TAM toxicity with an order of potency of myxothiazol ≥ stigmatellin > rotenone > antimycin A, suggesting a cell-specific cytotoxic interplay between mitochondrial complex I and III function and TAM action.
authors.affiliation: Institute of Physical Chemistry, NCSR Demokritos, Patriarchou Gregoriou & Neapoleos, Attiki, Greece. theo@chem.demokritos.gr
authors.forename: Theodossis Athanassios
authors.initials: TA
authors.lastname: Theodossiou
authors.forename: Konstantina
authors.initials: K
authors.lastname: Yannakopoulou
authors.forename: Chrysie
authors.initials: C
authors.lastname: Aggelidou
authors.forename: John Stephen
authors.initials: JS
authors.lastname: Hothersall
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009928:Organ Specificity; D011090:Polyenes / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D008689:Methacrylates; D011090:Polyenes; D011960:Receptors, Estrogen; D013844:Thiazoles; D012402:Rotenone; D013629:Tamoxifen; D000968:Antimycin A; C030517:myxothiazol; C041573:stigmatellin; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III