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Edelfosine in Membrane Environment - the Langmuir Monolayer Studies

The monolayer experiments proved the existence of strong interactions between edelfosine and cholesterol as well as ganglioside. Both these lipids are present in tumor membrane, however, their content changes during tumor development in a different way. Cholesterol concentration is often higher in normal versus edelfosine-sensitive tumor membranes. On the other hand, gangliosides concentration in normal membranes is very low, but it is increasing progressively with tumor progression.

Let us first analyze the potential role of cholesterol in the mechanism of selectivity of this drug. Among all the lipids studied in mixed Langmuir monolayers with edelfosine, cholesterol was found to interact with this drug most strongly. It has been also found that the strongest interactions occur at 1:1 proportion of edelfosine-to-cholesterol and it was suggested that these strong interactions provoke immobilization of edelfosine molecules in membrane [51], forming “surface complexes” composed of both molecules in 1:1 stiochiometry. These findings may be of help in understanding the results of experiments published by Diomede et al., [70-72] and Busto et al., [56]. In vitro experiments on cancer cells proved that the sensitivity of cells to edelfosine may be related to the concentration of sterol in a membrane. Namely, membranes of higher sterol content were found to incorporate edelfosine more slowly as well as the cell line resistant to the action of edelfosine (K562) was of a higher sterol concentration in biomembrane as compared to cell membrane sensitive to edelfosine (HL60). It was also evidenced that upon decreasing of sterol content in K562 cell membrane, it is possible to make the cell sensitive to edelfosine. To explain these results, the Langmuir monolayer experiments are of great importance. Namely, these experiments proved [51] high affinity of cholesterol to edelfosine, which becomes “immobilized” in the form of very stable “surface complexes” with cholesterol. Therefore, only a small amount of “free” (unbound) drug can permeate through cellular membrane, exerting its therapeutic activity. This finding indicates that i) the pharmacological activity of edelfosine may vary among different types of cells, depending on their cholesterol level in the plasma membrane, and ii) the cholesterol level must be precisely controlled when exposing cancer cells to edelfosine.

In a similar way the previously mentioned results for binary cholesterol/PC monolayers [60] can be explained. Since cholesterol/DPPC monolayers were of a higher proportion of cholesterol, strong sterol-drug interactions may explain stabilizing effect of edelfosine on these monolayers and they significantly contribute to the interactions found for ternary system. In the case of cholesterol/POPC monolayers, edelfosine may rather disturb cholesterol/POPC interactions than effectively interact with cholesterol, which is in a low concentration in the mixture. In summary, it can be concluded that a high proportion of cholesterol in membranes disturbs the incorporation of edelfosine and makes the cell resistant to the drug.

On the other hand, cholesterol is a component of lipid rafts, which have been suggested to be a site of action of edelfosine. It has been found that considerable amount of edelfosine taken up by Human T lymphoid leukemic Jurkat cells is incorporated into rafts and cover significant amount of total lipids content in raft [73]. The accumulation of edelfosine in rafts was also found for multiple myeloma cell [74], Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) [75]. Moreover, it was evidenced that edelfosine may affect rafts, changing drastically their organization and properties [73, 76]. Depletion of cholesterol in rafts inhibits the incorporation of edelfosine and thus the drug effectiveness [75]. It was also suggested that the effect of edelfosine on membrane rafts can be related to the formation of complexes between edelfosine and cholesterol [73].

It should be mentioned herein that although in Langmuir monolayer experiments rather weak affinity of edelfosine to

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sphingomyelin was evidenced [54], however, this compound - being a key component of membrane rafts - seems to be strongly required for the antitumor activity of edelfosine. Unquestionable role of this lipid was evidenced in the studies on mouse lymphoma cells [77]. Edelfosine was found to induce apoptosis in S49 cells by raft-dependent internalization, while it was found to be inactive towards a cell line variant (S49AR), which is unable to synthesize sphingomyelin.

It is clear that cholesterol - as lipid rafts component - is a crucial molecule for the activity of edelfosine and its strong interactions with the drug play a significant role in its mode of action. It seems that the presence of cholesterol in biomembrane and the existence of cholesterol-containing rafts is required for edelfosine activity. As is was proved, the increase of membrane cholesterol content inhibits incorporation of the drug into membrane. It is known, however, that cholesterol and membrane rafts are present also in healthy cells. This raises a question whether the level of cholesterol is the only factor controlling the effect of edelfosine on membranes? In another words, whether natural selectivity of edelfosine is connected only with differences in the fluidity between normal and tumor cells (regulated also by the sterol concentration) or perhaps there is another factor (like particular membrane component(s)), which additionally assists in this drug selectivity?

3.3. Is there any Target Molecule for Edelfosine Incorporation?

Tumorigenicity is related to the modification of the composition of normal versus tumor cell membranes, namely the concentration of some of components decreases, while the other increases with tumor progression. Thus, it is worth considering if the presence or absence of some lipids in a tumor membrane may additionally facilitate the uptake of edelfosine into the cell. To the best of our knowledge, the studies in this area have not been performed systematically. A good starting point for these investigations are the results of the Langmuir monolayer experiments aimed at investigating the role of gangliosides in the selectivity of edelfosine. When the interactions between edelfosine and various membrane lipids were studied in monolayers, strong affinity between the drug molecules and ganglioside was found [54]. The edelfosine-ganglioside interactions were nearly as strong as those between edelfosine and cholesterol. This finding induced further monolayer experiments on the potential role of this group of lipids in edelfosine selectivity [65]. The investigations were additionally encouraged by the fact that gangliosides are present in rafts as well as - although they are minor components of normal membranestheir concentration increases with tumor progression.

From the monolayer experiments on multicomponent systems composed of cholesterol/sphingomyelin/ganglioside/edelfosine, it is evident that there is a clear relationship between the content of ganglioside (measured in the range 1-20%) in the mixed system and the effect exerted by edelfosine on the system.

The issue concerning the role of ganglioside in the selectivity of edelfosine requires further analysis, although the results presented herein may be of help to design more complex studies. Moreover, we believe that the search for the target molecule among membrane components, differing tumor and normal membranes, is a right way to understand the issue of edelfosine selectivity.

4. OTHER THERAPEUTIC APPLICATIONS OF EDELFOSINE STUDIED WITH LANGMUIR MONOLAYERS

Although edelfosine - in principle - is used for treatments of cancer, it may also be useful to combat diseases caused by a number of pathogenic parasites, including a number of Leishmania, Trypanosoma and Entamoeba species [78-80]. In this regard, edelfosine was studied in mixed Langmuir monolayers with amphotericin B, in short AmB (polyene antibiotic, applied in

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conventional antileishmanian treatment), in order to verify its effect in combined antiparasitic therapy [81]. The idea of administering both drugs together was inspired by the fact that the application of AmB alone is accompanied by serious side effects resulting from drug’s toxicity, while the treatment with alkyl-lysophospholipids (e.g. edelfosine) alone is highly expensive and additionally these compounds exhibit much lower therapeutic activity than AmB. Another problem is the occurrence of the resistance to both drugs. In the first step of investigations, edelfosine and AmB were cospread in Langmuir monolayers and the obtained results revealed the existence of strong interactions between both molecules, leading to complex formation. Then, the influence of both drugs and their mixtures on model sterol/phospholipid erythrocyte and parasite membrane have been studied. The results proved low effect of drug mixture (as compared to AmB alone) on erythrocyte membrane, indicating that the combined therapy is less toxic versus AmB treatment. Moreover, edelfosine/AmB mixture was observed to exert a destabilizing effect on model parasite membrane, and the presence of AmB enhanced the effect induced by ED alone. Thus, with the aid of the monolayer technique, the combined antileishmanian therapy involving both drugs has been confirmed to be more beneficial than the separate treatment with either ED or AmB.

Edelfosine has also been used in the treatment of autoimmune diseases, such as chronic relapsing experimental allergic encephalomyelitis (EAE) [82] in animals and HIV [83] in human, however, this issue has not been verified so far with the Langmuir monolayer technique.

CONFLICT OF INTEREST

The author(s) confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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