Characterization of the interaction of doxorubicin with (poly)phosphoinositides in model systems Evidence for specific interaction with phosphatidylinositol-monophosphate and -diphosphate

• Published in: FEBS letters 1991-08, Vol.288 (1-2), p.237-240
• Main Authors: de Wolf, Frits A., Demel, Rudy A., Bets, Danny, van Kats, Carlos, de Kruijff, Ben
• Format: Article
• Language: English
• Subjects: (bovine brain) phosphatidylinositol; (dioleoyl or sn-1-stearoyl-2-arachidonoyl species of) phosphatidic acid, phophatidylcholine; (DO)PA, (SA)PA, (DO)PC; 1,4-piperazine-diethanesulfonic acid; Anionic phospholipid; Antineoplastic agents; Biological and medical sciences; di-(aminoethyl)-glycolether-N,N,N′,N′-tetraacetic acid; Doxorubicin; Doxorubicin - metabolism; Drug stacking; Drug—membrane interaction; EGTA; General aspects; Kinetics; Magnetic Resonance Spectroscopy; Medical sciences; Membrane penetration; Membranes - metabolism; Neomycin - metabolism; Pharmacology. Drug treatments; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols - metabolism; Phosphoinositide; PIP; PIP2, PI-4-phosphate and PI-4,5-diphosphate; PIPES; small unilamellar vesicles prepared by sonication; Spectrometry, Fluorescence; SUV
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/0014-5793(91)81043-8

The anticancer drug doxorubicin penetrates into Langmuir monolayers containing phosphoinositides. Upon binding of doxorubicin to phosphoinositide-containing SUV, its fluorescence is self-quenched due to self-association. As compared to other anionic phospholipids, as much as 2- to 3-fold larger effects were obtained with PIP and PIP2, in mixtures of these lipids with DOPC. Doxorubicin competes efficiently with the non-penetrating antibiotic neomycin for binding to PIP2. According to its penetration, specific binding of doxorubicin was half-maximal at 5–15 μM. It is likely that also in biological membranes doxorubicin binds specifically to PIP and PIP2.