Effects of lysosomotropic detergents on the human malarial parasite plasmodium falciparum in in vitro culture

Cabantchik, Z. I.; Silfen, J.; Firestone, Raymond A.; Krugliak, Miriam; Nissani, Edna; Ginsburg, Hagaï

doi:10.1016/0006-2952(89)90333-x

Cited by 11 publications

(7 citation statements)

References 19 publications

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“…Furthermore, the LD50 values reported for A␤ toxicity are closely correlated with the critical concentration we have determined for micelle formation by A␤ Soreghan et al, 1994), and both values do not change as the length of the peptide increases from 1-36 to 1-42. Surprisingly, the effects of lysosomotropic amphipathic agents on the lysosomal membrane are not due to a direct solubilization of the lysosomal membrane (Cabantchik et al, 1989;Forster et al, 1987), but rather are due to oxidative damage to the membrane (Cabantchik et al, 1989;Forster et al, 1987).…”

Section: Discussionmentioning

confidence: 98%

Loss of endosomal/lysosomal membrane impermeability is an early event in amyloid A?1-42 pathogenesis

et al. 1998

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Previous studies have implicated the failure to degrade aggregated Abeta1-42 in late endosomes or secondary lysosomes as a mechanism for the accumulation of beta-amyloid in Alzheimer's disease. We examined the consequences of intracellular accumulation of Abeta1-42 on the integrity of the endosomal/lysosomal compartment by monitoring Lucifer Yellow fluorescence and the release of lysosomal hydrolases into the soluble, cytosolic fraction. In control cells, the Lucifer Yellow fluorescence is observed as punctate staining in a perinuclear distribution with no apparent cytoplasmic fluorescence, consistent with its localization in late endosomes or secondary lysosomes. After incubation with Abeta1-42 for 6 hr, a loss of lysosomal membrane impermeability is observed as evidenced by redistribution of the fluorescence to a diffuse, cytoplasmic pattern. The loss of lysosomal membrane impermeability is correlated with Abeta1-42 accumulation, since incubation of the cells with the nonaccumulating isoform of amyloid, Abeta1-40, does not induce leakage. The same results were obtained using the release of soluble lysosomal hydrolases, cathepsin D and beta-hexosaminidase, into the cytosol as an assay for the leakage of lysosomal contents. Together, our results suggest that the loss of lysosomal membrane impermeability may be an early event in Abeta pathogenesis, and provide an explanation for the miscompartmentalization of extracellular and cytoplasmic components observed in Alzheimer's disease (AD). The release of hydrolases may further cause the breakdown of the cytoskeleton and the blebbing of the plasma membrane, and the leakage of heparan sulfate glycosaminoglycans from the lysosome may ultimately promote the assembly of tau into neurofibrillary tangles (NFT).

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Section: Discussionmentioning

confidence: 98%

Loss of endosomal/lysosomal membrane impermeability is an early event in amyloid A?1-42 pathogenesis

et al. 1998

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“…It was further hypothesized that at sufficiently high concentrations they destabilize the lysosomal membrane, eventually leading to leakage of the lysosomal content, and ultimately to cell death . The cytotoxicity of the LD types originally devised by Firestone, is well documented, including N -dodecylimidazole, − N -dodecylmorpholine, and fluorinated N -dodecylamines . Also serine alkylamides , as well as structurally very different compounds such as siramesine are cytotoxic LDs.…”

Section: Introductionmentioning

confidence: 99%

“…Also serine alkylamides , as well as structurally very different compounds such as siramesine are cytotoxic LDs. Additionally, LDs have been demonstrated to exert antimalarial and antifungal , properties.…”

Section: Introductionmentioning

confidence: 99%

“…However, no further explanation or reason for this difference was provided . Similarly, Cabantchik and co-workers failed to observe any detergent-like action of LDs on the acidic compartments of malarial parasites . Siramesine destabilizes the lysosomal membrane, but is structurally different from alkyl LDs, and while it partitions into bilayers, it also binds to acidic phospholipid headgroups with high affinity, and sequestering of acidic lipids has been suggested as an alternative mechanism by which it contributes to cell toxicity …”

Section: Introductionmentioning

confidence: 99%

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Spontaneous Vesiculation and pH-Induced Disassembly of a Lysosomotropic Detergent: Impacts on Lysosomotropism and Lysosomal Delivery

et al. 2016

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Lysosomotropic detergents (LDs) selectively rupture lysosomal membranes through mechanisms that have yet to be characterized. A consensus view, currently, holds that LDs, which are weakly basic, diffuse across cellular membranes as monomers in an uncharged state, and via protonation in the acidic lysosomal compartment, they become trapped, accumulate, and subsequently solubilize the membrane and induce lysosomal membrane permeabilization. Here we demonstrate that the lysosomotropic detergent O-methyl-serine dodecylamide hydrochloride (MSDH) spontaneously assembles into vesicles at, and above, cytosolic pH, and that the vesicles disassemble as the pH reaches 6.4 or lower. The aggregation commences at concentrations below the range of those used in cell studies. Assembly and disassembly of the vesicles was studied via dynamic light scattering, zeta potential measurements, cryo-TEM, and fluorescence correlation spectroscopy and was found to be reversible via control of the pH. Aggregation of MSDH into closed vesicles under cytosolic conditions is at variance with the commonly held view of LD behavior, and we propose that endocytotic pathways should be considered as possible routes of LD entry into lysosomes. We further demonstrate that MSDH vesicles can be loaded with fluorophores via a solution transition from low to high pH, for subsequent release when the pH is lowered again. The ability to encapsulate molecular cargo into MSDH vesicles together with its ability to disaggregate at low pH and to permeabilize the lysosomal membrane presents an intriguing possibility to use MSDH as a delivery system.

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“…Furthermore, there is a broad range of concentrations at which vacuolation becomes apparent, spanning several orders of magnitude [ 10 , 18 – 20 ]. In addition, there are monobasic amines that do not exhibit any vacuolation-inducing behavior [ 6 , 9 , 10 , 13 , 14 , 21 ], and do not compete with the lysosomal uptake of other lysosomotropic probes [ 6 , 16 ], or that are cytotoxic [ 21 ]. Most importantly, some lysosomotropic molecules have been reported to accumulate in other organelles, such as mitochondria [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Simulation-based cheminformatic analysis of organelle-targeted molecules: lysosomotropic monobasic amines

Zhang

Zheng

Rosania

2008

J Comput Aided Mol Des

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Cell-based molecular transport simulations are being developed to facilitate exploratory cheminformatic analysis of virtual libraries of small drug-like molecules. For this purpose, mathematical models of single cells are built from equations capturing the transport of small molecules across membranes. In turn, physicochemical properties of small molecules can be used as input to simulate intracellular drug distribution, through time. Here, with mathematical equations and biological parameters adjusted so as to mimic a leukocyte in the blood, simulations were performed to analyze steady state, relative accumulation of small molecules in lysosomes, mitochondria, and cytosol of this target cell, in the presence of a homogenous extracellular drug concentration. Similarly, with equations and parameters set to mimic an intestinal epithelial cell, simulations were also performed to analyze steady state, relative distribution and transcellular permeability in this non-target cell, in the presence of an apicalto-basolateral concentration gradient. With a test set of ninety-nine monobasic amines gathered from the scientific literature, simulation results helped analyze relationships between the chemical diversity of these molecules and their intracellular distributions.

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Effects of lysosomotropic detergents on the human malarial parasite plasmodium falciparum in in vitro culture

Cited by 11 publications

References 19 publications

Loss of endosomal/lysosomal membrane impermeability is an early event in amyloid A?1-42 pathogenesis

Loss of endosomal/lysosomal membrane impermeability is an early event in amyloid A?1-42 pathogenesis

Spontaneous Vesiculation and pH-Induced Disassembly of a Lysosomotropic Detergent: Impacts on Lysosomotropism and Lysosomal Delivery

Simulation-based cheminformatic analysis of organelle-targeted molecules: lysosomotropic monobasic amines

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