Differential impact of synthetic antitumor lipid drugs on the membrane organization of phosphatidic acid and diacylglycerol monolayers

Antitumor lipid (ATL) drugs exhibit unique amphiphilic and selectivity properties that make them attractive for cancer treatment. Being synthetic derivatives of lysophosphatidylcholine, these drugs also demonstrate both antimicrobial and antiparasitic activity as well as cytotoxic/cytostatic effects in cancer cells, which make them suitable for alleviating side effects associated with cancer treatments. To date, three antitumor lipid drugs, namely, edelfosine, miltefosine, and perifosine have been extensively studied for various cancer treatment applications. However, the mechanism of action of these drugs has not been fully explored. A careful look at previous research studies showed that they preferentially partition into the rigid lipid domains, alter the membrane organization, and disrupt the normal cell processes to cause the death of the cells – an assertion that is yet to be fully agreed upon by scientists.

Ideally, monolayer studies can be used to investigate the biophysical changes in the lateral domain organization as well as lipid packing and stability, which according to the recent research, can give more insights on the mode of action for ATL drugs. To this note, Canadian researchers at the University of Calgary: Dr. Mark Mahadeo and Professor Elmar Prenner, investigated the biophysical effects of synthetic ATL drugs on the membrane organization of phosphatidic acid and diacylglycerol monolayers. Their objective was to understand how these lipids affect the mechanism of action these drugs. Their work is currently published in the journal, Chemistry and Physics of Lipids. The authors stated that phosphatidic acid and diacylglycerol were chosen for this study due to previous work by their collaborators showing that these lipids effected the susceptibility of yeast cells to these drugs.

In their approach, the biophysical effects of three ATL drugs: edelfosine, miltefosine, and perifosine on the monolayers were carefully studied and compared. A combination of surface pressure, compression moduli, and Brewster angle microscopy techniques were used to evaluate the packing stability and lateral organization of these films. Moreover, an equimolar mixture of the phosphatidic acid and diacylglycerol monolayers was introduced to obtain more insights into the relationship between the monolayers and the synthetic ATL drugs.

The authors observed that the synthetic ATL drugs exhibited different interactions with the monolayers. They found that both the edelfosine and miltefosine demonstrated remarkable stabilizing effects on all the monolayers, while perifosine destabilized the equimolar mixture and the dimyristoyl glycerol monolayers. In addition, all three drugs changed the morphology of the observed domains. However, the mechanism of action for edelfosine and miltefosine drugs were noted to be plausibly similar and dependent on their high stabilizing effects on the monolayers. On the other hand, the mode of action of perifosine could be attributed to the direct inhibition of specific signal transduction. The authors also concluded that perifosine may illicit cytotoxicity through a different mechanism compared to the other antitumor lipid drugs.

In summary, the study evaluated the underlying action mechanism of three ATL drugs by investigating their differential impact on the membrane organization of the monolayers. The team found out that all the three drugs changed the morphology of the observed domains even though perifosine actioned differently compared to edelfosine and miltefosine. In a statement to the Medicine Innovates, the authors said that understanding better the mode of action of the synthetic ATL drugs will advance the development of better antitumor lipid drugs. According to Dr. Mahadeo “a better understanding of membrane organization, and the causes of its disruption, will hopefully go a long way in aiding the discovery of better treatments.”