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

Significance 

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.”

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

About the author

Dr. Prenner is a Professor in the Department of Biological Sciences at the University of Calgary contributing to the biochemistry and nanoscience programs. He received an MSc Degree in biochemistry and his PhD in biochemistry from the University of Technology in Graz. His research at the Department of Biochemistry focused on the investigation of the lateral architecture and lipid domain formation in erythrocyte membrane using time-resolved fluorescence spectroscopy under the guidance of Albin Hermetter. Subsequently, he was supported by an EMBO postdoctoral fellowship to work with Dietmar Möbius at the Max-Planck-Institute for Biophysical Chemistry on biologically relevant applications of their newly developed method of Brewster angle microscopy.

 Next he joined Karl Lohner at the Austrian Academy of Science using biophysical methods to study the membrane interactions of antimicrobial peptides. Finally, he was supported by the Alberta Heritage Foundation for Medical Research (AHFMR) as a postdoctoral fellow to work on the membrane interactions of antimicrobial peptides with Ronald McElhaney at the University of Alberta. The continuation of the research in the McElhaney group was supported by the Protein Engineering Network of Centers of Excellence directed by Robert Hodges at the University of Alberta. In 2002, again supported by AHFMR, Dr. Prenner joined the Department of Biological Sciences at the University of Calgary as a faculty member.

His research focuses on membrane biophysics, bionanotechnology including nanoparticle based pulmonary drug delivery and bioanalytical chemistry by investigating the impact of toxic and essential metals on biomembrane structure and function. Dr. Prenner has published over 90 papers and holds 3 patents. He served as reviewer for over sixty journals in multiple disciplines and is on the editorial board of Biochim. Biophys. Acta – Biomembranes. This research was funded by federal (NSERC, CIHR) and provincial funding agencies (AHFMR, CRIO) and has also resulted in spin-off companies that successfully commercialize fluorescence based devices and bioassays.

About the author

Dr. Mark Mahadeo is a Canadian scientist whose research interests involve cellular membrane organization and lipid drug interactions. Dr. Mahadeo received his B.Sc in biochemistry from the University of Calgary in 2010 and his Ph.D in biophysical chemistry from the University of Calgary in 2017. During his doctoral studies, the focus of his research was investigating how a class of synthetic lipid analogue anti cancer drugs affected lipid membrane organization. This research was conducted under the supervision of Dr. Elmar J Prenner at the University of Calgary, supported in part through funding by the provincial government of Alberta to Dr. Mahadeo and funding through the federal government of Canada via a NSERC discovery grant to Dr. Prenner.  Dr. Mahadeo has contributed to publications, reviews and book chapters focusing on the use of biophysical techniques to study lipid drug interactions and membrane organization.

He has presented at numerous international conferences and has taught courses at the undergraduate level, for which he has received teaching awards at the institutional level. Dr. Mahadeo is currently a Post doctoral scholar working in the lab of Dr. Jenifer Thewalt at Simon Fraser University, where his research continues to involve lipid and membrane structure and organization.

Reference

Mahadeo, M., & Prenner, E. (2020). Differential impact of synthetic antitumor lipid drugs on the membrane organization of phosphatidic acid and diacylglycerol monolayersChemistry and Physics of Lipids, 229, 104896.

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