scholarly journals Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death

2014 ◽  
Vol 42 (5) ◽  
pp. 1460-1464 ◽  
Author(s):  
Ana M. Villamil Giraldo ◽  
Hanna Appelqvist ◽  
Thomas Ederth ◽  
Karin Öllinger
Keyword(s):  
Cell Death ◽  
Regulatory Mechanism ◽  
Current Knowledge ◽  
Hydrolytic Enzymes ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Lysosomal Membrane Permeabilization ◽  
Amphiphilic Compounds ◽  
Lysosomal Stability ◽  
Acidic Organelles

Lysosomes are acidic organelles essential for degradation, signalling and cell homoeostasis. In addition, they play a key role in cell death. Permeabilization of the lysosomal membrane and release of hydrolytic enzymes to the cytosol accompanies apoptosis signalling in several systems. The regulatory mechanism of lysosomal stability is, however, poorly understood. Lipophilic or amphiphilic compounds with a basic moiety will become protonated and trapped within lysosomes, and such lysosomotropic behaviour is also found in many pharmacological drugs. The natural sphingolipid sphingosine exhibits lysosomotropic detergent ability and is an endogenous candidate for controlling lysosomal membrane permeabilization. The lysosomotropic properties of certain detergents might be of use in lysosome-targeting anticancer drugs and drug delivery system in the future. The present review summarizes the current knowledge on the targeting and permeabilizing properties of lysosomotropic detergents from a cellular and physicochemical perspective.

Lysosomal membrane permeabilization as a cell death mechanism in cancer cells

2018 ◽  
Vol 46 (2) ◽  
pp. 207-215 ◽  
Author(s):  
Ana Serrano-Puebla ◽  
Patricia Boya
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Proteolytic Enzymes ◽  
Hydrolytic Enzymes ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Lysosomal Membrane Permeabilization ◽  
Regulated Cell Death ◽  
Cathepsin Activity ◽  
Intracellular Cascades

Lysosomes are acidic organelles that contain hydrolytic enzymes that mediate the intracellular degradation of macromolecules. Damage of these organelles often results in lysosomal membrane permeabilization (LMP) and the release into the cytoplasm of the soluble lysosomal contents, which include proteolytic enzymes of the cathepsin family. This, in turn, activates several intracellular cascades that promote a type of regulated cell death, called lysosome-dependent cell death (LDCD). LDCD can be inhibited by pharmacological or genetic blockade of cathepsin activity, or by protecting the lysosomal membrane, thereby stabilizing the organelle. Lysosomal alterations are common in cancer cells and may increase the sensitivity of these cells to agents that promote LMP. In this review, we summarize recent findings supporting the use of LDCD as a means of killing cancer cells.

scholarly journals Increased Lysosomal Membrane Permeabilization in Oxidant-exposed Macrophages of Human Fibrotic Lungs

2013 ◽  
Vol 6 ◽  
pp. JCD.S13271 ◽  
Author(s):  
Hans L Persson ◽  
Linda K. Vainikka
Keyword(s):  
Cell Death ◽  
Lung Fibrosis ◽  
Reduced Glutathione ◽  
Atomic Absorption Spectrophotometry ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Blue Staining ◽  
Green Fluorescence ◽  
Lysosomal Membrane Permeabilization ◽  
Typical Morphology

A disrupted balance of reduced glutathione (GSH) and iron (Fe) and subsequent enhanced susceptibility of lysosomes of lung macrophages (LMs) to oxidants may play a role in lung fibrogenesis. We assessed cellular Fe/GSH, lysosomal membrane permeabilization (LMP), and cell death in cultures of oxidant exposed LMs. LMs from 7 lung fibrosis patients and healthy subjects were exposed to a physiologic concentration of H2O2 for 1 h. LMP was assessed with acridine orange green fluorescence, apoptosis/necrosis were estimated by apoptotic DNA and typical morphology, Fe was assessed with Prussian blue staining/atomic absorption spectrophotometry, and GSH was evaluated using a GSH assay kit. Oxidant-induced LMP and cell death were more pronounced in cultures of LMs from patients with lung fibrosis, and these cells contained less GSH and more cytochemically stained Fe. These observations indicate that LMP may be involved in fibrosis development, possibly through activation of the inflammasome complex. Further studies are warranted for a detailed understanding.

Lysosomes in programmed cell death pathways: from initiators to amplifiers

2017 ◽  
Vol 398 (3) ◽  
pp. 289-301 ◽  
Author(s):  
Nežka Kavčič ◽  
Katarina Pegan ◽  
Boris Turk
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Inflammasome Activation ◽  
Biological Macromolecules ◽  
Lysosomal Hydrolases ◽  
Lysosomal Membrane Permeabilization ◽  
Cell Death Pathways ◽  
Major Attention

Abstract Lysosome is the central organelle for intracellular degradation of biological macromolecules and organelles. The material destined for degradation enters the lysosomes primarily via endocytosis, autophagy and phagocytosis, and is degraded through the concerted action of more than 50 lysosomal hydrolases. However, lysosomes are also linked with numerous other processes, including cell death, inflammasome activation and immune response, as well as with lysosomal secretion and cholesterol recycling. Among them programmed cell death pathways including apoptosis have received major attention. In most of these pathways, cell death was accompanied by lysosomal membrane permeabilization and release of lysosomal constituents with an involvement of lysosomal hydrolases, including the cathepsins. However, it is less clear, whether lysosomal membrane permeabilization is really critical for the initiation of cell death programme(s). Therefore, the role of lysosomal membrane permeabilization in various programmed cell death pathways is reviewed, as well as the mechanisms leading to it.

scholarly journals Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Patricia Dauer ◽  
Vineet K. Gupta ◽  
Olivia McGinn ◽  
Alice Nomura ◽  
Nikita S. Sharma ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Lysosomal Membrane Permeabilization ◽  
Er Homeostasis

GDC-0941 enhances the lysosomal compartment via TFEB and primes glioblastoma cells to lysosomal membrane permeabilization and cell death

2013 ◽  
Vol 329 (1) ◽  
pp. 27-36 ◽  
Author(s):  
Stefanie Enzenmüller ◽  
Patrick Gonzalez ◽  
Georg Karpel-Massler ◽  
Klaus-Michael Debatin ◽  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Glioblastoma Cells ◽  
Lysosomal Compartment ◽  
Lysosomal Membrane Permeabilization

scholarly journals Lysosomal Membrane Permeabilization Induces Cell Death in a Mitochondrion-dependent Fashion

2003 ◽  
Vol 197 (10) ◽  
pp. 1323-1334 ◽  
Author(s):  
Patricia Boya ◽  
Karine Andreau ◽  
Delphine Poncet ◽  
Naoufal Zamzami ◽  
Jean-Luc Perfettini ◽  
...  
Keyword(s):  
Cell Death ◽  
Uv Light ◽  
Chromatin Condensation ◽  
Cell Loss ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Cytotoxic Action ◽  
Double Knockout ◽  
Lysosomal Membrane Permeabilization ◽  
Mitochondrial Membrane Permeabilization

A number of diseases are due to lysosomal destabilization, which results in damaging cell loss. To investigate the mechanisms of lysosomal cell death, we characterized the cytotoxic action of two widely used quinolone antibiotics: ciprofloxacin (CPX) or norfloxacin (NFX). CPX or NFX plus UV light (NFX*) induce lysosomal membrane permeabilization (LMP), as detected by the release of cathepsins from lysosomes. Inhibition of the lysosomal accumulation of CPX or NFX suppresses their capacity to induce LMP and to kill cells. CPX- or NFX-triggered LMP results in caspase-independent cell death, with hallmarks of apoptosis such as chromatin condensation and phosphatidylserine exposure on the plasma membrane. LMP triggers mitochondrial membrane permeabilization (MMP), as detected by the release of cytochrome c. Both CPX and NFX* cause Bax and Bak to adopt their apoptotic conformation and to insert into mitochondrial membranes. Bax−/− Bak−/− double knockout cells fail to undergo MMP and cell death in response to CPX- or NFX-induced LMP. The single knockout of Bax or Bak (but not Bid) or the transfection-enforced expression of mitochondrion-targeted (but not endoplasmic reticulum–targeted) Bcl-2 conferred protection against CPX (but not NFX*)-induced MMP and death. Altogether, our data indicate that mitochondria are indispensable for cell death initiated by lysosomal destabilization.

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