Lysosomotropic agents. 1. Synthesis and cytotoxic action of lysosomotropic detergents

Firestone, Raymond A.; Pisano, Judith M.; Bonney, Robert J.

doi:10.1021/jm00195a026

Cited by 125 publications

(107 citation statements)

References 6 publications

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“…1A). 37 Furthermore, our recent in vitro studies confirm that siramesine is an amphiphilic compound that partitions into the air/water interface and binds to acidic phospholipids with high affinity thereafter penetrating into the hydrocarbon core of the membrane (Parry MJ, Alakoskela J-MI, Jäättelä M, Mahalka A, Kinnunen PKJ, unpublished data). Finally, the characteristics of siramesine-induced cell death, e.g., an early lysosome damage occurring prior to cell rounding and death, dependence on cysteine cathepsin activity and cell density as well as a highly sigmoidal dose-response curve, 10 closely resemble those of other lysosomotropic detergents.…”

Section: Discussionmentioning

confidence: 76%

“…Finally, the characteristics of siramesine-induced cell death, e.g., an early lysosome damage occurring prior to cell rounding and death, dependence on cysteine cathepsin activity and cell density as well as a highly sigmoidal dose-response curve, 10 closely resemble those of other lysosomotropic detergents. 36,38 It should, however, be noted that whereas other lysosomotropic detergents have been reported to kill all lysosome-containing cells, 37 siramesine-mediated killing displays selectivity to transformed cells both in vitro and in vivo. 10,18 Our earlier data showing that siramesine induces oxidative stress and that lipophilic but not hydrophilic anti-oxidants effectively inhibit siramesine-induced cell death have suggested that lipid peroxidation may be involved in siramesine-induced lysosomal leakage and cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

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Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation

Ostenfeld¹,

Høyer-Hansen²,

Bastholm³

et al. 2008

Autophagy

140

120

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A σ-2 receptor ligand siramesine induces lysosomal leakage and cathepsin-dependent death of cancer cells in vitro and displays potent anti-cancer activity in vivo. The mechanism by which siramesine destabilizes lysosomes is, however, unknown. Here, we show that siramesine induces a rapid rise in the lysosomal pH that is followed by lysosomal leakage and dysfunction. The rapid accumulation of siramesine into cancer cell lysosomes, its ability to destabilize isolated lysosomes, and its chemical structure as an amphiphilic amine indicate that it is a lysosomotropic detergent. Notably, siramesine triggers also a substantial Atg6-and Atg7-dependent accumulation of autophagosomes that is associated with a rapid and sustained inhibition of mammalian target of rapamycin complex 1 (mTORC1; an inhibitor of autophagy). Siramesine fails, however, to increase the degradation rate of long-lived proteins. Thus, the massive accumulation of autophagosomes is likely to be due to a combined effect of activation of autophagy signaling and decreased autophagosome turnover. Importantly, pharmacological and RNA interference-based inhibition of autophagosome formation further sensitizes cancer cells to siramesine-induced cytotoxicity. These data identify siramesine as a lysosomotropic detergent that triggers cell death via a direct destabilization of lysosomes and cytoprotection by inducing the accumulation of autophagosomes. Threrefore, the combination of siramesine with inhibitors of autophagosome formation appears as a promising approach for future cancer therapy.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation

Ostenfeld¹,

Høyer-Hansen²,

Bastholm³

et al. 2008

Autophagy

140

120

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“…It has also been suggested that damaged entire lysosomes can be autophagocytozed (Stroikin et al 2004;Kiffin et al 2006). Regardless of the mechanism of autophagic sequestration, it does not prevent apoptosis of MSDH-treated cells (Li et al 2000), since the acidic interior of autophagolysosomes is attracting MSDH, which at low pH becomes protonated and acquires properties of a detergent (Firestone et al 1979). …”

Section: Discussionmentioning

confidence: 99%

Lysosome-targeted stress reveals increased stability of lipofuscin-containing lysosomes

Stroikin

Mild

Johansson

et al. 2008

AGE

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Cellular ageing is associated with accumulation of undegradable intralysosomal material, called lipofuscin. In order to accelerate the lipofuscin accumulation, confluent, growth-arrested human fibroblasts were cultured under hyperoxic conditions. To provide a better insight into the effects of lipofuscin on cellular functions, we compared lysosomal stability in control and lipofuscin-loaded human fibroblasts under conditions of lysosometargeted stress induced by exposure to either the lysosomotropic detergent MSDH or the redox-cycling quinone naphthazarin. We show that lysosomal damage, assessed by acridine-orange relocation, translocation of cathepsin D to the cytosol, and alkalinization of lysosomes, is more pronounced in control than in lipofuscin-loaded fibroblasts. Finding that lysosomal integrity was less affected or even preserved in case of lipofuscin-loaded cells enables us to suggest that lipofuscin exerts lysosome-stabilizing properties.

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“…acid phosphatase, β-glucuronidase and cathepsin B, into the cytoplasm (Boyer and Tannock, 1993). Furthermore, Firestone and co-workers proposed a novel approach to target tumour cells by utilizing lysosomal enzymes and synthesized a new class of agents termed lysosomotropic detergents (Firestone et al, 1979). These compounds are designed to be weakly basic so they concentrate within lysosomes as a result of the pH gradient across the lysosomal membrane.…”

Section: Discussionmentioning

confidence: 99%

Cellular uptake, cytotoxicity and DNA-binding studies of the novel imidazoacridinone antineoplastic agent C1311

et al. 1999

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Summary C1311 is a novel therapeutic agent with potent activity against experimental colorectal cancer that has been selected for entry into clinical trial. The compound has previously been shown to have DNA-binding properties and to inhibit the catalytic activity of topoisomerase II. In this study, cellular uptake and mechanisms by which C1311 interacts with DNA and exerts cytotoxic effects in intact colon carcinoma cells were investigated. The HT29 colon cancer cell line was chosen to follow cellular distribution of C1311 over a time course of 24 h at drug concentrations that just inhibited cell proliferation by 50% or 100%. Nuclear uptake of C1311 and co-localization with lysosomal or mitochondrial dyes was examined by fluorescence microscopy and effects on these cellular compartments were determined by measurement of acid phosphatase levels, rhodamine 123 release or DNA-binding behaviour. The strength and mode of DNA binding was established by thermal melting stabilization, direct titration and viscometric studies of host duplex length. The onset of apoptosis was followed using a TUNEL assay and DNA-fragmentation to determine a causal relationship of cell death. Growth inhibition of HT29 cells by C1311 was concomitant with rapid drug accumulation in nuclei and in this context we showed that the compound binds to duplex DNA by intercalation, with likely A/T sequence-preferential binding. Drug uptake was also seen in lysosomes, leading to lysosomal rupture and a marked increase of acid phosphatase activity 8 h after exposure to C1311 concentrations that effect total growth inhibition. Moreover, at these concentrations lysosomal swelling and breakdown preceded apoptosis, which was not evident up to 24 h after exposure to drug. Thus, the lysosomotropic effect of C1311 appears to be a novel feature of this anticancer agent. As it is unlikely that C1311-induced DNA damage alone would be sufficient for cytotoxic activity, lysosomal rupture may be a critical component for therapeutic efficacy.Keywords: C1311; HT29 cells; colorectal cancer; cytotoxicity; DNA intercalation; lysosomes 367British Journal of Cancer (1999) 81(2), 367-375 © 1999 Cancer Research Campaign Article no. bjoc.1999 Received MATERIALS AND METHODS Materials/DrugsThe 5-(ω-aminoalkyl)amino-8-hydroxyimidazoacridinone C1311 (Figure 1) was synthesized at the Technical University of Gdansk, as described elsewhere (Cholody et al, 1990(Cholody et al, , 1992. Stock solutions were prepared in dimethyl sulphoxide (DMSO) or normal saline. Aqueous solutions were prepared in polystyrene tubes to minimize adsorption effects and quantified by spectrophotometry. Hoechst 33258 dye (Sigma-Aldrich Ltd) was used as a control ligand for viscometric studies and quantified using ε 338 = 42 000 M -1 cm -1 (Loontiens et al, 1990). All DNA binding experiments were performed in aqueous phosphate buffer (10 mM NaH 2 PO 4 /Na 2 HPO 4 , 1 mM Na 2 EDTA, pH 7.00 ± 0.01). Doublestranded calf thymus DNA (CT-DNA, type-I [Sigma-Aldrich Ltd.]) was sonicated and purified using a publ...

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Lysosomotropic agents. 1. Synthesis and cytotoxic action of lysosomotropic detergents

Cited by 125 publications

References 6 publications

Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation

Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation

Lysosome-targeted stress reveals increased stability of lipofuscin-containing lysosomes

Cellular uptake, cytotoxicity and DNA-binding studies of the novel imidazoacridinone antineoplastic agent C1311

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