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Weak base drug-induced endolysosome iron dyshomeostasis controls the generation of reactive oxygen species, mitochondrial depolarization, and cytotoxicity.
- Source :
- NeuroImmune Pharmacology & Therapeutics; Mar2024, Vol. 3 Issue 1, p33-46, 14p
- Publication Year :
- 2024
-
Abstract
- Approximately 75 % of marketed drugs have the physicochemical property of being weak bases. Weak-base drugs with relatively high pK<subscript>a</subscript> values enter acidic organelles including endosomes and lysosomes (endolysosomes), reside in and de-acidify endolysosomes, and induce cytotoxicity. Divalent cations within endolysosomes, including iron, are released upon endolysosome de-acidification. Endolysosomes are "master regulators of iron homeostasis", and neurodegeneration is linked to ferrous iron (Fe<superscript>2+</superscript>)-induced reactive oxygen species (ROS) generation via Fenton chemistry. Because endolysosome de-acidification-induced lysosome-stress responses release endolysosome Fe<superscript>2+</superscript>, it was crucial to determine the mechanisms by which a functionally and structurally diverse group of weak base drugs including atropine, azithromycin, fluoxetine, metoprolol, and tamoxifen influence endolysosomes and cause cell death. Using U87MG astrocytoma and SH-SY5Y neuroblastoma cells, we conducted concentration-response relationships for 5 weak-base drugs to determine EC<subscript>50</subscript> values. From these curves, we chose pharmacologically and therapeutically relevant concentrations to determine if weak-base drugs induced lysosome-stress responses by de-acidifying endolysosomes, releasing endolysosome Fe<superscript>2+</superscript> in sufficient levels to increase cytosolic and mitochondria Fe<superscript>2+</superscript> and ROS levels and cell death. Atropine (anticholinergic), azithromycin (antibiotic), fluoxetine (antidepressant), metoprolol (beta-adrenergic), and tamoxifen (anti-estrogen) at pharmacologically and therapeutically relevant concentrations (1) de-acidified endolysosomes, (2) decreased Fe<superscript>2+</superscript> levels in endolysosomes, (3) increased Fe<superscript>2+</superscript> and ROS levels in cytosol and mitochondria, (4) induced mitochondrial membrane potential depolarization, and (5) increased cell death; effects prevented by the endocytosed iron-chelator deferoxamine. Weak-base pharmaceuticals induce lysosome-stress responses that may affect their safety profiles; a better understanding of weak-base drugs on Fe<superscript>2+</superscript> interorganellar signaling may improve pharmacotherapeutics. [ABSTRACT FROM AUTHOR]
- Subjects :
- HOMEOSTASIS
REACTIVE oxygen species
MITOCHONDRIAL DNA
LYSOSOMES
PHARMACOLOGY
Subjects
Details
- Language :
- English
- ISSN :
- 27506665
- Volume :
- 3
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- NeuroImmune Pharmacology & Therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 176252450
- Full Text :
- https://doi.org/10.1515/nipt-2023-0021