Evidence of a complex between adriamycin derivatives and cardiolipin: Possible role in cardiotoxicity

Most of the mitochondrial damage induced by antimitotic drugs of the adriamycin family could be due to the high affinity of these drugs for the membrane. The prime interaction between the anthracycline drug and this membrane would explain specific alterations observed on mitochondria. Cardiolipin has been proposed as a privileged target. We have tested this hypothesis here. Model membranes (lipid monolayers, liposomes) were used to demonstrate the interaction between these anthracycline drugs and different phospholipids. A new surface potential technique showed the specificity of adriamycin derivatives for cardiolipin whereas no complexation was observed with neutral phospholipids (dipalmitoyl lecithin and egg lecithin). Association constants were evaluated and a good correlation was obtained between the mitochondrial toxicity of each drug and its affinity for cardiolipin. Fluorescence measurements were carried out in order to locate precisely the position of the drug in the lipid bilayer. Perturbations of the lipid organization after complex formation were analysed using phospholipase A2 as an enzymic probe.