Tilorone-induced lysosomal storage of sulphated glycosaminoglycans can be separated from tilorone-induced enhancement of lysosomal enzyme secretion

Lüllmann‐Rauch, Renate; Pods, R.; Witzendorff, Burkhard von

doi:10.1016/0006-2952(95)00042-x

Cited by 15 publications

(8 citation statements)

References 38 publications

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“…This result was due to an increase in intracellular enzyme activity (results not shown) which thus made a larger contribution to the total activity. Similar results were previously obtained with low tilorone concentrations [4]. At…”

Section: Dose-response Curve For Lysosomal Enzyme Secretionsupporting

confidence: 90%

“…The lysosomes become cut off from the supply of new enzymes and, as a result, various types of nondegraded macromolecules pile up [34]. This rather unspecific lysosomal storage has to be distinguished from the GAG storage that occurs at lower drug concentrations that do not enhance secretion of lysosomal enzyme [4].…”

Section: Discussionmentioning

confidence: 99%

“…After freezing and thawing, the cellular material was subjected to ultrasonication. The activity of β-hexosaminidase (EC 3.2.1.52) was determined photometrically in medium and cell lysates as described previously [4], with 4-methylumbelliferyl N-acetyl-β-glucosaminide as substrate. To account for β-hexosaminidase activity contributed by the fetal calf serum in the medium, each experiment included two flasks containing medium without cells.…”

Section: Enzyme Assaymentioning

confidence: 99%

“…Dicationic amphiphilic compounds such as tilorone ( Figure 1a) and congeners are accumulated in lysosomes, interfere with the lysosomal degradation of sulphated glycosaminoglycans (GAGs) and cause lysosomal storage of GAGs, predominantly dermatan sulphate [1][2][3][4]. Drug-induced GAG storage has been described in rats and cultured cells of rat, ox and man [1][2][3][4][5][6][7]. Its occurrence in of a lysosomal enzyme (β-hexosaminidase, EC 3.2.1.52), the ability of MT to cause storage of [$&S]GAGs was significantly lower than that of tilorone.…”

Section: Introductionmentioning

confidence: 99%

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Tilorone-induced lysosomal lesions: the bisbasic character of the drug is essential for its high potency to cause storage of sulphated glycosaminoglycans

Fischer

Hein

Lüllmann‐Rauch

et al. 1996

Biochemical Journal

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The immunomodulatory agent tilorone -2,7-bis-[2-(diethyl-amino)ethoxy]fluoren-9-one- and congeners are potent inducers of lysosomal storage of sulphated glycosaminoglycans (GAGs) in animals and cultured fibroblasts of animals and man. All potent inducers of GAG storage hitherto described are bisbasic polycyclic aromatic compounds. They are accumulated in lysosomes and disturb the degradation of GAGs, mainly dermatan sulphate. It has been proposed that the drugs cross-link the polyanionic GAG chains giving rise to undergradable drug-GAG complexes. This hypothesis implies that the bisbasic character of the drug molecules is essential for the side effect in question. In the present study, this was tested by comparing tilorone and its monobasic derivative (MT) with respect to (i) induction of GAG storage in cultured bovine corneal fibroblasts and (ii) physicochemical interactions with GAGs in vitro. The intralysosomal concentration of MT achieved after 1-3 days was of the same order of magnitude as previously shown for tilorone. Nevertheless, under conditions that did not enhance the secretion of a lysosomal enzyme (beta-hexosaminidase, EC 3.2.1.52), the ability of MT to cause storage of [35S]GAGs was significantly lower than that of tilorone. Morphological observations showed that MT was much more potent in causing lysosomal storage of polar lipids than of GAGs. CD spectroscopy with tilorone revealed that the presence of GAGs caused the primarily achiral drug molecules to display CD. This suggested a helical orientation of the tilorone molecules within GAG-drug complexes, and short intermolecular distances which allowed electronic coupling of the aromatic ring systems of adjacent drug molecules. In contrast, MT failed to display any induced optical activity, indicating the absence of highly ordered GAG-drug complexes. In conclusion, the present results show that the substitution of the planar aromatic ring system with two basic side chains is essential for the high potency of tilorone in inducing lysosomal GAG storage. This is paralleled by, and presumably causally related to, strong physicochemical interactions with GAGs.

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Section: Dose-response Curve For Lysosomal Enzyme Secretionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Enzyme Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tilorone-induced lysosomal lesions: the bisbasic character of the drug is essential for its high potency to cause storage of sulphated glycosaminoglycans

Fischer

Hein

Lüllmann‐Rauch

et al. 1996

Biochemical Journal

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“…3). Others have shown that the tilorone induced glycosaminoglycans storage can be separated from the tilorone induced secretion of lysosomal enzymes (47). The lysosomotropic mechanism may also have an important role as tilorone blocks viral entry.…”

Section: Lysosomotropic Mechanismmentioning

confidence: 99%

Tilorone: a Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and beyond

2020

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History and Morphology of the Lysosome

Lüllmann‐Rauch

Lysosomes

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Tilorone-induced lysosomal storage of sulphated glycosaminoglycans can be separated from tilorone-induced enhancement of lysosomal enzyme secretion

Cited by 15 publications

References 38 publications

Tilorone-induced lysosomal lesions: the bisbasic character of the drug is essential for its high potency to cause storage of sulphated glycosaminoglycans

Tilorone-induced lysosomal lesions: the bisbasic character of the drug is essential for its high potency to cause storage of sulphated glycosaminoglycans

Tilorone: a Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and beyond

History and Morphology of the Lysosome

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