Effects of quinacrine on endothelial cell morphology and transcription factor-DNA interactions.
Quinacrine has been used for decades and the beneficial effects of this drug are as numerous as its toxic effects. Since endothelial cells (EC) are in many cases the first cells coming in contact with drugs, the effect of quinacrine on certain aspects of EC biology were studied. The presented data demonstrate that quinacrine can have a marked impact on the integrity on EC monolayer without grossly interfering with cell viability. The described impact of quinacrine on EC might explain, at least in part, the toxic effects of this drug observed in the past. Furthermore, quinacrine profoundly effects gene regulation in EC. Quinacrine binds to DNA in a sequence-specific manner. While NF-kappa B-DNA interactions are not effected, AP-1-DNA binding is blocked by quinacrine. Such differential effects are presumably due to intercalation of quinacrine into the AP-1 consensus element. Preincubation of oligonucleotides resembling this sequence blocked the subsequent binding of nuclear extract containing AP-1 protein(s). Taken together, these data suggest that quinacrine interferes with EC physiology and alters the repertoire of EC to respond to stimuli. Furthermore, the differential effects of quinacrine might be exploited to study and gain additional insight in the involvement of AP-1 and NF-kappa B in gene regulation.
Stuhlmeier
K M
KM
Ludwig Boltzmann Institute for Rheumatology and Balneology, Kurbadstrasse 10, A-1100 Vienna, Austria. karlms@excite.com
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007364:Intercalating Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011796:Quinacrine / Q000494:pharmacology*; D013552:Swine; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha
D019040:E-Selectin; D007364:Intercalating Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D011796:Quinacrine