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Article

The Lysosomotropic Activity of Hydrophobic Weak Base Drugs is Mediated via Their Intercalation into the Lysosomal Membrane

1
The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel
2
BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
*
Author to whom correspondence should be addressed.
Cells 2020, 9(5), 1082; https://doi.org/10.3390/cells9051082
Received: 5 March 2020 / Revised: 11 April 2020 / Accepted: 20 April 2020 / Published: 27 April 2020
(This article belongs to the Section Organelle Function)
Lipophilic weak base therapeutic agents, termed lysosomotropic drugs (LDs), undergo marked sequestration and concentration within lysosomes, hence altering lysosomal functions. This lysosomal drug entrapment has been described as luminal drug compartmentalization. Consistent with our recent finding that LDs inflict a pH-dependent membrane fluidization, we herein demonstrate that LDs undergo intercalation and concentration within lysosomal membranes. The latter was revealed experimentally and computationally by (a) confocal microscopy of fluorescent compounds and drugs within lysosomal membranes, and (b) molecular dynamics modeling of the pH-dependent membrane insertion and accumulation of an assortment of LDs, including anticancer drugs. Based on the multiple functions of the lysosome as a central nutrient sensory hub and a degradation center, we discuss the molecular mechanisms underlying the alteration of morphology and impairment of lysosomal functions as consequences of LDs’ intercalation into lysosomes. Our findings bear important implications for drug design, drug induced lysosomal damage, diseases and pertaining therapeutics. View Full-Text
Keywords: lysosomes; lysosomotropic drugs; drug sequestration; membrane intercalation; molecular dynamics lysosomes; lysosomotropic drugs; drug sequestration; membrane intercalation; molecular dynamics
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MDPI and ACS Style

Stark, M.; Silva, T.F.D.; Levin, G.; Machuqueiro, M.; Assaraf, Y.G. The Lysosomotropic Activity of Hydrophobic Weak Base Drugs is Mediated via Their Intercalation into the Lysosomal Membrane. Cells 2020, 9, 1082. https://doi.org/10.3390/cells9051082

AMA Style

Stark M, Silva TFD, Levin G, Machuqueiro M, Assaraf YG. The Lysosomotropic Activity of Hydrophobic Weak Base Drugs is Mediated via Their Intercalation into the Lysosomal Membrane. Cells. 2020; 9(5):1082. https://doi.org/10.3390/cells9051082

Chicago/Turabian Style

Stark, Michal, Tomás F. D. Silva, Guy Levin, Miguel Machuqueiro, and Yehuda G. Assaraf. 2020. "The Lysosomotropic Activity of Hydrophobic Weak Base Drugs is Mediated via Their Intercalation into the Lysosomal Membrane" Cells 9, no. 5: 1082. https://doi.org/10.3390/cells9051082

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