Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death

Giraldo, Ana M. Villamil; Appelqvist, Hanna; Ederth, Thomas; Öllinger, Karin

doi:10.1042/bst20140145

Cited by 115 publications

(81 citation statements)

References 46 publications

(52 reference statements)

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“…Rapid inhibition of lysosomal acidification by CEP (as early as 5 min) (Fig. 3I) suggests that, as an amphiphilic cation, it may directly enter the lysosomes and modulate pH, an effect similar to that seen with lysosomotropic agents [41]. This possibility has been proposed previously [42].…”

Section: Discussionsupporting

confidence: 61%

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Lyu

Yang

Head³

et al. 2017

Cancer Letters

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Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents.

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Section: Discussionsupporting

confidence: 61%

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Lyu

Yang

Head³

et al. 2017

Cancer Letters

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“…Compared to healthy B-lymphocytes, elevated levels of sphingosine render CLL cells more prone to lysosome perturbation [17]. Sphingosine can also be converted by two sphingosine-kinase isoforms (SPHK1 and SPHK2) to form sphingosine-1-phosphate, which generally exerts antiapoptotic and prosurvival properties [18]. Overall, changes in lysosome structure in cancer cells sensitize them to LMP and may result in cell death.…”

Section: Introductionmentioning

confidence: 99%

Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy

Domagała

Fidyt

Bobrowicz

et al. 2018

IJMS

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Lysosomes are conservative organelles with an indispensable role in cellular degradation and the recycling of macromolecules. However, in light of recent findings, it has emerged that the role of lysosomes in cancer cells extends far beyond cellular catabolism and includes a variety of cellular pathways, such as proliferation, metastatic potential, and drug resistance. It has been well described that malignant transformation leads to alterations in lysosomal structure and function, which, paradoxically, renders cancer cells more sensitive to lysosomal destabilization. Furthermore, lysosomes are implicated in the regulation and execution of cell death in response to diverse stimuli and it has been shown that lysosome-dependent cell death can be utilized to overcome apoptosis and drug resistance. Thus, the purpose of this review is to characterize the role of lysosome in cancer therapy and to describe how these organelles impact treatment resistance. We summarized the characteristics of typical inducers of lysosomal cell death, which exert its function primarily via alterations in the lysosomal compartment. The review also presents other anticancer agents with the predominant mechanism of action different from lysosomal destabilization, the activity of which is influenced by lysosomal signaling, including classical chemotherapeutics, kinase inhibitors, monoclonal antibodies, as well as photodynamic therapy.

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“…Disruption of lysosomal morphology and activity can be a consequence of osmotic or direct membrane lysis (Repnik et al, 2014;Villamil Giraldo et al, 2014). In the case of osmotic lysis, a relatively high quantity of soluble compounds is trapped in the lumen, thereby increasing the osmotic pressure.…”

Section: Lysosomotropic Agentsmentioning

confidence: 99%

“…Another important factor in the sphingosine detergent activity seems to be also cathepsin B, which degrades sphingosine into the anti-apoptotic sphingosine 1-phosphate. In addition, sphingosine membranolytic properties depend on pH and lipid composition (Johansson et al, 2010;Young et al, 2013;Villamil Giraldo et al, 2014). In addition, destabilization of lysosomal membrane can be mediated also by non-permeable compounds that accumulate in lysosomes after delivery by endocytosis (Aits and Jaattela, 2013;Repnik et al, 2014;Villamil Giraldo et al, 2014).…”

Section: Lysosomotropic Agentsmentioning

confidence: 99%

Lysosomes in programmed cell death pathways: from initiators to amplifiers

Kavčič

Pegan

Turk

2016

Biological Chemistry

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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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Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death

Cited by 115 publications

References 46 publications

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy

Lysosomes in programmed cell death pathways: from initiators to amplifiers

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