DISRUPTION OF CELLULAR SIGNALING PATHWAYS BY DAUNOMYCIN THROUGH DESTABILIZATION OF NONLAMELLAR MEMBRANE STRUCTURES

Albeit anthracyclines are widely used in the treatment of solid tumors and leukemias, their mechanism of action has not been elucidated. The present study gives relevant information about the role of nonlamella r membrane structures in signaling pathways, which could explain how a nthracyclines can exert their cytocidal action without entering the ce ll [Tritton, T.R. and Yee, G, (1982) Science 217, 248-250]. The anthra cycline daunomycin reduced the formation of the nonlamellar hexagonal (H-II) phase (i.e., the hexagonal phase propensity), stabilizing the b ilayer structure of the plasma membrane by a direct interaction with m embrane phospholipids. As a consequence, various cellular events invol ved in signal transduction, such as membrane fusion and membrane assoc iation of peripheral proteins [e.g., guanine nucleotide-binding regula tory proteins (G proteins and protein kinase C-cup)], where nonlamella r structures (negative intrinsic monolayer curvature strain) are requi red, were altered by the presence of daunomycin. Functionally, daunomy cin also impaired the expression of the high-affinity state of a G pro tein-coupled receptor (ternary complex for the alpha(2)-adrenergic rec eptor) due to G-protein dissociation from the plasma membrane. In vivo , daunomycin also decreased the levels of membrane-associated G protei ns and protein kinase C-alpha beta in the heart. The occurrence of suc h nonlamellar structures favors the association of these peripheral pr oteins with the plasma membrane and prevents daunomycin-induced dissoc iation. These results reveal an important role of the lipid component of the cell membrane in signal transduction and its alteration by anth racyclines.