Weak Base Drug-induced Endolysosome Iron Dyshomeostasis Controls the Generation of Reactive Oxygen Species, Mitochondrial Depolarization, and Cytotoxicity

Overview

Journal NeuroImmune Pharm Ther

Date 2024 Mar 27

PMID 38532786

Authors

Peter W Halcrow

Darius N K Quansah

Nirmal Kumar

Rebecca L Solloway

Kayla M Teigen

Kasumi A Lee

Braelyn Liang

Jonathan D Geiger

Affiliations

Soon will be listed here.

Abstract

Objectives: Approximately 75 % of marketed drugs have the physicochemical property of being weak bases. Weak-base drugs with relatively high pK 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)-induced reactive oxygen species (ROS) generation via Fenton chemistry. Because endolysosome de-acidification-induced lysosome-stress responses release endolysosome Fe, 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.

Methods: Using U87MG astrocytoma and SH-SY5Y neuroblastoma cells, we conducted concentration-response relationships for 5 weak-base drugs to determine EC 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 in sufficient levels to increase cytosolic and mitochondria Fe and ROS levels and cell death.

Results: 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 levels in endolysosomes, (3) increased Fe 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.

Conclusions: Weak-base pharmaceuticals induce lysosome-stress responses that may affect their safety profiles; a better understanding of weak-base drugs on Fe interorganellar signaling may improve pharmacotherapeutics.

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