Effects of quinacrine on endothelial cell morphology and transcription factor-DNA interactions

Quinacrine has been used for decades and the beneficial effects of this dru g 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 qui nacrine on certain aspects of EC biology were studied. The presented data d emonstrate that quinacrine can have a marked impact on the integrity on EC monolayer without grossly interfering with cell viability. The described im pact of quinacrine on EC might explain, at least in part, the toxic effects of this drug observed in the past. Furthermore, quinacrine profoundly effe cts gene regulation in EC. Quinacrine binds to DNA in a sequence-specific m anner. While NF-KB-DNA interactions are not effected, AP-1-DNA binding is b locked by quinacrine. Such differential effects are presumably due to inter calation of quinacrine into the AP-1 consensus element. Preincubation of ol igonucleotides resembling this sequence blocked the subsequent binding of n uclear extract containing AP-1 protein(s). Taken together, these data sugge st that quinacrine interferes with EC physiology and alters the repertoire of EC to respond to stimuli. Furthermore, the differential effects of quina crine might be exploited to study and gain additional insight in the involv ement of AP-1 and NF-KB in gene regulation. (C) 2000 Elsevier Science B.V. All rights reserved.