Disruption of cellular signaling pathways by daunomycin through destabilization of nonlamellar membrane structures.

Abstract

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 nonlamellar membrane structures in signaling pathways, which could explain how anthracyclines can exert their cytocidal action without entering the cell [Tritton, T. R. & Yee, G. (1982) Science 217,[248][249][250]. The anthracycline daunomycin reduced the formation of the nonlamellar hexagonal (Hn) phase (i.e., the hexagonal phase propensity), stabilizing the bilayer structure of the plasma membrane by a direct interaction with membrane phospholipids. As a consequence, various cellular events involved in signal transduction, such as membrane fusion and membrane association of peripheral proteins [e.g., guanine nucleotide-binding regulatory proteins (G proteins and protein kinase C-a*3)], where nonlamellar structures (negative intrinsic monolayer curvature strain) are required, were altered by the presence of daunomycin. Functionally, daunomycin also impaired the expression of the high-affinity state of a G protein-coupled receptor (ternary complex for the a2-adrenergic receptor) due to G-protein dissociation from the plasma membrane. In vivo, daunomycin also decreased the levels of membrane-associated G proteins and protein kinase C-a.3 in the heart. The occurrence of such nonlamellar structures favors the association of these peripheral proteins with the plasma membrane and prevents daunomycin-induced dissociation. These results reveal an important role of the lipid component of the cell membrane in signal transduction and its alteration by anthracyclines.Anthracyclines are potent antitumor drugs. They bind with high affinity to DNA (1), causing a stabilization of the DNA double helix (2). Although a mechanism of anthracycline cytotoxicity based on their interaction with DNA has been proposed, strong evidence has accumulated suggesting the involvement of the plasma membrane in the cytotoxic action of these antitumor drugs. The plasma membrane is the first cellular target found by anthracyclines, and it is able to bind a large number of drug molecules (3, 4), so that a primary action on the physicochemical properties of the cell membrane could trigger a series of events responsible for their cytotoxic effect (5). Anthracyclines with little or no ability to bind to DNA, such as N-trifluoroacetyladriamycin 14-valerate (AD 32), exhibit a good antitumor activity, which argues against DNAmediated effects (6). A number of physicochemical properties of the plasma membrane are affected by anthracyclines (3, 5, 7), and agarose-linked doxorubicin (former generic name, adriamycin) is able to kill cells, without penetrating them, solely by its interaction with the plasma membrane (8). Despite all these indications that the antitumor activity of anthracyclines originates from their interaction with cellular membranes, the mechanism of cytotoxicity has not been elucidated. Here we present evidence that nonlamellar membra...

The Gβγ Dimer Drives the Interaction of Heterotrimeric Gi Proteins with Nonlamellar Membrane Structures

“…Thus, PE-rich domains or regions with negative curvature strain, in either a stable or a transient manner, could act as membrane reservoirs for these peripheral proteins. This finding is in agreement with the observed loss of G proteins from brain plasma membranes after the disruption of nonlamellar H II structures by the anthracycline daunomycin (18).…”

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

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“…In this context, anthracyclines that are unable to enter cancer cells or bind to DNA still have strong antitumor activity (6). Indeed, those used in human therapy regulate plasma membrane structure, and they induce changes in the localization and activity of important peripheral signaling proteins, such as G proteins and PKC (4,7,8). This mode of action also appears to be responsible for the activity of hexamethylene bisacetamide against cancers (9,10).…”

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