Differential impact of synthetic antitumor lipid drugs on the membrane organization of phosphatidic acid and diacylglycerol monolayers
| Autor: | Mark Mahadeo, Elmar J. Prenner |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
030303 biophysics
Phosphatidic Acids Antineoplastic Agents Biochemistry Diglycerides Membrane Lipids 03 medical and health sciences chemistry.chemical_compound Membrane Microdomains medicine Cytotoxicity Molecular Biology 030304 developmental biology Diacylglycerol kinase Microscopy 0303 health sciences Organic Chemistry Cell Biology Phosphatidic acid Perifosine Lysophosphatidylcholine chemistry Mechanism of action Biophysics lipids (amino acids peptides and proteins) medicine.symptom Signal transduction Edelfosine |
| Zdroj: | Chemistry and Physics of Lipids. 229:104896 |
| ISSN: | 0009-3084 |
| DOI: | 10.1016/j.chemphyslip.2020.104896 |
| Popis: | Anti-tumour lipids are synthetic analogues of lysophosphatidylcholine. These drugs are both cytotoxic and cytostatic, and more interestingly, exert these effects preferentially in tumour cells. While the exact mechanism of action isn’t fully elucidated, these drugs appear to preferentially partition into rigid lipid domains in cell membranes. Upon insertion, the compounds alter membrane domain organization, disrupt normal signal transduction, and cause cell death. Recently, it has been reported that these drugs induce accumulation of diacylglycerol in yeast cells which in turn sensitizes cells to the drugs. Conversely, phosphatidic acid accumulation appears to protect cells against the drugs. In the current work, the aim was to compare the biophysical effects of the drugs edelfosine, miltefosine and perifosine on monolayers of dimyristoyl phosphatidic acid, dimyristoyl glycerol and an equimolar mixture, to understand how these lipids modulate the mode of action. Surface pressure – area isotherms, compression moduli and Brewster angle microscopy were used to compare drug effects on lipid packing, monolayer compressibility and lateral domain organization of these films. Results suggest that edelfosine and miltefosine have stabilizing effects on all of the monolayers, while perifosine destabilizes dimyristoyl glycerol and the equimolar mixture. Additionally, all three drugs change the morphology of the domains observed. Based on these results the stabilization of diacylgylcerol by edelfosine and miltefosine may contribute to the mode of action as diacylglycerol is a known disruptor of bilayers. Perifosine however does not stabilize diacylglycerol, and therefore cell death may occur through a more direct inhibition of specific signal transduction. These results suggest that perifosine may illicit cytotoxicity through a different mechanism compared to the other antitumor lipid drugs. |
| Databáze: | OpenAIRE |
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