Lysosomal storage of sulfated glycosaminoglycans in cultured fibroblasts exposed to immunostimulatory acridine derivatives.
The purpose of the present cytological and radiochemical study was to investigate whether the immunomodulatory agent 3,6-bis[2-(diethylamino)ethoxy]acridine (CL-90.100) and three congeners induce lysosomal storage of sulfated glycosaminoglycans (sGAG) in cultured rat corneal fibroblasts. The reason for asking this question was as follows: The four acridine derivatives have molecular similarities with the dicationic amphiphilic compound tilorone, which has previously been shown to cause sGAG storage in cultured cells and in intact rats. The cells were exposed to the drugs for 72 hr. Tilorone served as reference. All acridine derivatives caused cytological alterations which, on the basis of the cytochemical results, were indicative of lysosomal sGAG storage. The threshold concentrations ranged from 0.3 to 0.7 microM. Radiochemical experiments showed that CL-90.100 up to 10 microM induced [35S]GAG storage in a dose-dependent manner, with an EC50 of 2 microM. Concentrations above 10 microM were cytotoxic. Experiments with equimolar concentrations (3 microM) demonstrated that three of the acridine derivatives were more potent and one was less potent than tilorone. Additionally, CL-90.100 was tested on bovine corneal fibroblasts, with cytochemical and radiochemical results similar to those in rat cells. The present findings show that (a) the four acridine derivatives induce lysosomal sGAG storage; (b) the acridine ring, compared with the fenfluorenone ring (tilorone), enhances this potency; and (c) the substituents at the nitrogens can have some influence on the potency to induce sGAG storage.
Handrock
K
K
Department of Anatomy, University of Kiel, Germany.
Laschke
A
A
Lüllmann-Rauch
R
R
Vogt
R D
RD
Ziegenhagen
M
M
D000166:Acridines / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003315:Cornea / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006025:Glycosaminoglycans / Q000493:pharmacokinetics*; D007424:Intracellular Fluid / Q000378:metabolism; D007700:Kinetics; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008854:Microscopy, Electron; D051381:Rats; D013045:Species Specificity; D013462:Sulfur Radioisotopes; D013994:Tilorone / Q000494:pharmacology
D000166:Acridines; D000276:Adjuvants, Immunologic; D006025:Glycosaminoglycans; D013462:Sulfur Radioisotopes; C013786:A73025; C075219:3,6-bis(2-(diethylamino)ethoxy)acridine; D013994:Tilorone