Amiodarone impairs trafficking through late endosomes inducing a Niemann-Pick C-like phenotype

Abstract

Patients treated with amiodarone accumulate lysobisphosphatidic acid (LBPA), also known as bis(monoacylglycero)phosphate, in airway secretions and develop in different tissues vacuoles and inclusion bodies thought to originate from endosomes. To clarify the origin of these changes, we studied in vitro the effects of amiodarone on endosomal activities like transferrin recycling, Shiga toxin processing, ESCRT-dependent lentivirus budding, fluid phase endocytosis, proteolysis and exosome secretion. Furthermore, since the accumulation of LBPA might point to a broader disturbance in lipid homeostasis, we studied the effect of amiodarone on the distribution of LBPA, unesterified cholesterol, sphingomyelin and glycosphyngolipids. Amiodarone analogues were also studied, including the recently developed derivative dronedarone. We found that amiodarone does not affect early endosomal activities, like transferrin recycling, Shiga toxin processing and lentivirus budding. Amiodarone, instead, interferes with late compartments of the endocytic pathway, blocking the progression of fluid phase endocytosis and causing fusion of organelles, collapse of lumenal structures, accumulation of undegraded substrates and amassing of different types of lipids. Not all late endocytic compartments are affected, since exosome secretion is spared. These changes recall the Niemann-Pick type-C phenotype (NPC), but originate by a different mechanism, since, differently from NPC, they are not alleviated by cholesterol removal. Studies with analogues indicate that basic pKa and high water-solubility at acidic pH are crucial requirements for the interference with late endosomes/lysosomes and that, in this respect, dronedarone is at least as potent as amiodarone. These findings may have relevance in fields unrelated to rhythm control.

High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs

“…Quinacrine uptake by cultured human vascular smooth muscle cells or in undifferentiated U937 monoblastoid cells, equally dependent on V-ATPase activity, was comparable in many respects to that of peripheral blood PMNLs, but of lower apparent affinity (K M 8.7 µM and 14.8 µM, respectively) and LC3 accumulation occurred at a somewhat higher drug concentration than in PMNLs (present study vs. Marceau et al, 2009;2013). Cells loaded with amines do not exhibit a detectable nutritional deprivation (Marceau et al, 2012) and the lack of resolution of the vacuolar cytopathology has been likened to Niemannlysosomal storage disease (Piccoli et al, 2011), a loss of function of the lysosomal degradation capacity of the cell. Whether this impacts on immunity is unclear at the present time.…”

Antiviral activity of cationic amphiphilic drugs

“…Finally, it has been suggested that different CADs can induce the same cellular phenotype, by targeting specific substrates, but with a different mechanism of action. Indeed, U18666A and amiodarone induce a NPC-like phenotype with the formation of enlarged vacuoles enriched in BMP, cholesterol removal alleviates the change in BMP distribution induced by U18666A, but not the one induced by amiodarone suggesting a different mechanism of action [17].…”

“…The cellular uptake mechanisms markedly differ between different CADs. Indeed, they can accumulate into the Lys within minutes or hours after in vitro cell exposition and the different kinetic depends from the chemicalphysical characteristics of the molecules [13,[15][16][17]. The amine functional group of these compounds is mainly unprotonated at physiological pH.…”

Bioinformatics Approach to Screening and Developing Drug against Ebola

“…Amiodarone works by the induction of Niemann-Pick C-like phenotype that inhibits late endosomal entry of Ebola virus [37]. Sertraline and bepridil work in a similar fashion to amiodarone.…”