Drug-induced lysosomal storage of sulfated glycosaminoglycans. Studies on the underlying structure-activity relationships

Handrock, K.; Lüllmann-Rauch, R; Vogt, R.D.

doi:10.1016/0300-483x(93)90042-q

Cited by 10 publications

(5 citation statements)

References 18 publications

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“…To establish whether Tilorone induced lysosomal accumulation of GAGs, we measured the activity of b-Hexosaminidase, as secreted into the cell's medium. Secretion of b-Hexosaminidase from cells is consistent with impaired lysosomal activity (Handrock et al 1993;Lullmann-Rauch et al 1996). b-Hexosaminidase activity in the medium of Tilorone-treated CHO cells was about 50% higher as compared to control cells (not shown), in line with previously published results .…”

Section: Tilorone Treatment Inhibits the Clearance Of Prp Sc From Cellssupporting

confidence: 92%

“…Tilorone (2,7-bis[2-(diethylamino)ethoxy]-9-fluorenone dihydrochloride) purchased from sigma was dissolved in DDW and added to cells media at final concentration of 15 lM for 3 days as previously described (Handrock et al 1993). Subsequently, the cells were washed three times and returned to fresh media for further treatment.…”

Section: Treatment Of Cells With Tiloronementioning

confidence: 99%

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Chemically Induced Accumulation of GAGs Delays PrPSc Clearance but Prolongs Prion Disease Incubation Time

et al. 2008

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Prion diseases are a group of fatal neurodegenerative diseases affecting humans and animals. The only identified component of the infectious prion is PrP(Sc), an aberrantly folded isoform of PrP(C). Glycosaminoglycans, which constitute the main receptor for prions on cells, play a complex role in the pathogenesis of prion diseases. For example, while agents inducing aberrant lysosomal accumulation of GAGs such as Tilorone and Quinacrine significantly reduced PrP(Sc) content in scrapie-infected cells, administration of Quinacrine to prion-infected subjects did not improve their clinical status. In this study, we investigated the association of PrP(Sc )with cells cultured with Tilorone. We found that while the initial incorporation of PrP(Sc) was similar in the treated and untreated cells, clearance of PrP(Sc) from the Tilorone-treated cells was significantly impaired. Interestingly, prolonged administration of Tilorone to mice prior to prion infection resulted in a significant delay in disease onset, concomitantly with in vivo accumulation of lysosomal GAGs. We hypothesize that GAGs may complex with newly incorporated PrP(Sc) in lysosomes and further stabilize the prion protein conformation. Over-stabilized PrP(Sc) molecules have been shown to comprise reduced converting activity.

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Section: Tilorone Treatment Inhibits the Clearance Of Prp Sc From Cellssupporting

confidence: 92%

Section: Treatment Of Cells With Tiloronementioning

confidence: 99%

Chemically Induced Accumulation of GAGs Delays PrPSc Clearance but Prolongs Prion Disease Incubation Time

et al. 2008

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“…Exposure to the drug usually lasted 72 h, with no change of the culture medium. This time period was previously found to be most appropriate for inducing marked GAG storage with tilorone and its bisbasic analogues [7,14].…”

Section: Cell Cultures and Experimental Conditionsmentioning

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%

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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“…All potent inducers of lysosomal glycosaminoglycan storage so far described consist of a central aromatic ring system symmetrically substituted with two aliphatic side chains each carrying a secondary or tertiary nitrogen atom. The type of aromatic ring system seems to be non-critical as long as it is a bulky planar structure (Handrock et al 1993). In cultured fibroblasts exposed to tilorone and congeners, dermatan sulphate is the principal glycosaminoglycan which is accumulated (Fischer 1995).…”

mentioning

confidence: 99%

Lysosomal Storage of Sulphated Glycosaminoglycans Induced by Dicationic Amphiphilic Drug molecules: Significance of the Central Planar Ring System

Lüllmann‐Rauch

Witzendorff

1996

Pharmacology & Toxicology

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The immunomodulatory drug tilorone (2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one) and several congeners are known to disturb the lysosomal degradation of sulphated glycosaminoglycans and thereby induce lysosomal storage of glycosaminoglycans in cultured cells and intact organisms. The molecules of tilorone and congeners consist of a planar aromatic ring system symmetrically substituted with two aliphatic side chains each carrying a protonizable nitrogen. In a previous study it was proposed that non-degradable glycosaminoglycan-drug complexes are formed by electrostatic interactions and that additionally intermolecular interactions between the drug molecules due to electronic coupling of their central planar ring system are important for formation and stabilization of the glycosaminoglycan-drug complexes and thus for the drug side effect in question. The significance of the central planar ring system was tested in the present study by comparing tilorone and the compound bis(beta-diethylamino-ethylether)hexestrol (DH) with respect to their potencies to cause lysosomal glycosaminoglycan storage in cultured bovine corneal fibroblasts. DH has the same side chains as tilorone, but its central apolar moiety lacks planarity. At a concentration (1.75 muM) which did not cause enhanced secretion of the lysosomal enzyme beta-hexosaminidase (E.C. 3.2.1.52), DH was significantly less potent than tilorone in causing storage of [35S]glycosaminoglycans. This is taken as support of the hypothesis that the planar tricyclic ring system is essential for the high potency of tilorone and its congeners to exert this adverse action.

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Drug-induced lysosomal storage of sulfated glycosaminoglycans. Studies on the underlying structure-activity relationships

Cited by 10 publications

References 18 publications

Chemically Induced Accumulation of GAGs Delays PrPSc Clearance but Prolongs Prion Disease Incubation Time

Chemically Induced Accumulation of GAGs Delays PrPSc Clearance but Prolongs Prion Disease Incubation Time

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

Lysosomal Storage of Sulphated Glycosaminoglycans Induced by Dicationic Amphiphilic Drug molecules: Significance of the Central Planar Ring System

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