Ultrastructural and spectroscopic methods in the study of anthracycline-membrane interaction

Observations on the interaction of anthracycline antibiotics with the plasma membrane, performed by morphological, ultrastructural, microanalytical and spectroscopic methods, are reported and discussed in this review. Scanning and transmission electron microscopy analysis indicates that doxorubicin (DOX) induces dose-dependent modifications of the cell morphology and membrane ultrastructure of human erythrocytes. The formation of intramembrane particle-free domains on both the fracture faces of the plasma membrane suggests that the DOX molecules become incorporated within the lipid bilayer. Electron energy-loss spectroscopy measurements reveal a reduction in the P/C ratio in treated membranes, probably due to a phospholipid "dilution" following the incorporation of DOX molecules. The radiowave dielectric spectroscopy indicates modifications induced by DOX in the passive electrical properties of the membrane. In particular, the decrease in membrane conductivity suggests that the interaction of the drug with the membrane lipids can affect the function of specific ion channels. The results obtained allow us to propose a structural model of the DOX-membrane interaction, in which DOX molecules self-associate in the phospholipid bilayer. The DOX incorporation induces remarkable changes in the structural and functional properties of the plasma membrane, strengthening the hypothesis that this drug can also exert its cytotoxic action at the membrane level.