Verapamil prevents the effects of daunomycin on the thermotropic phase transition of model lipid bilayers

Abstract

High-sensitivity differential scanning calorimetry and fluorescence-depolarization techniques were used to study how the presence of daunomycin and/or verapamil affect the thermotropic behaviour of dipalmitoyl phosphatidylcholine (DPPC) vesicles. Daunomycin, a potent anti-cancer agent, perturbs the thermodynamic parameters associated with the lipid phase transition: it decreases the enthalpy change, lowers the transition temperature and reduces the co-operative behavior of the phospholipid molecules. Verapamil, on the other hand, produces smaller alterations in the lipid phase transition. However, when daunomycin and verapamil are present simultaneously in the DPPC vesicles, it is observed that verapamil prevents, in a concentration-dependent manner, the alteration in the phospholipid phase transition expected from the presence of daunomycin in the bilayer. Furthermore, drug-binding studies suggest that the observed interference of verapamil in the daunomycin/phospholipid interaction occurs without a decrease in the amount of daunomycin bound to the lipid bilayer and without the formation of a daunomycin-verapamil complex. Because of the importance of drug-membrane interactions in anthracycline cytotoxicity, we speculate that the lipid bilayer of biological membranes may provide appropriate sites at which the presence of verapamil influences the activity of daunomycin.