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 Triarylpyridine Compounds and Chloroquine Act in Concert to Trigger Lysosomal Membrane Permeabilization and Cell Death in Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1621
Author(s):  
Jennifer Beauvarlet ◽  
Rabindra Nath Das ◽  
Karla Alvarez-Valadez ◽  
Isabelle Martins ◽  
Alexandra Muller ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Membrane Damage ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Cancer Therapies ◽  
Quadruplex Dna ◽  
Lysosomal Membrane Permeabilization ◽  
G Quadruplex ◽  
Massive Cell Death

Lysosomes play a key role in regulating cell death in response to cancer therapies, yet little is known on the possible role of lysosomes in the therapeutic efficacy of G-quadruplex DNA ligands (G4L) in cancer cells. Here, we investigate the relationship between the modulation of lysosomal membrane damage and the degree to which cancer cells respond to the cytotoxic effects of G-quadruplex ligands belonging to the triarylpyridine family. Our results reveal that the lead compound of this family, 20A promotes the enlargement of the lysosome compartment as well as the induction of lysosome-relevant mRNAs. Interestingly, the combination of 20A and chloroquine (an inhibitor of lysosomal functions) led to a significant induction of lysosomal membrane permeabilization coupled to massive cell death. Similar effects were observed when chloroquine was added to three new triarylpyridine derivatives. Our findings thus uncover the lysosomal effects of triarylpyridines compounds and delineate a rationale for combining these compounds with chloroquine to increase their anticancer effects.

scholarly journals Natural Products Induce Lysosomal Membrane Permeabilization as an Anticancer Strategy

Medicines ◽  
2021 ◽  
Vol 8 (11) ◽  
pp. 69
Author(s):  
Reginald Halaby
Keyword(s):  
Cell Death ◽  
Natural Products ◽  
Global Health ◽  
Cancer Cells ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Economic Issue ◽  
Neoplastic Cells ◽  
Lysosomal Membrane Permeabilization ◽  
Dividing Cells

Cancer is a global health and economic issue. The majority of anticancer therapies become ineffective due to frequent genomic turnover and chemoresistance. Furthermore, chemotherapy and radiation are non-specific, killing all rapidly dividing cells including healthy cells. In this review, we examine the ability of some natural products to induce lysosomal-mediated cell death in neoplastic cells as a way to kill them more specifically than conventional therapies. This list is by no means exhaustive. We postulate mechanisms to explain lysosomal membrane permeabilization and its role in triggering cell death in cancer cells.

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.

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.

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