Alkylphospholipids are Signal Transduction Modulators with Potential for Anticancer Therapy

Abstract

Background:Alkylphospholipids (APLs) are synthetically derived from cell membrane components, which they target and thus modify cellular signalling and cause diverse effects. This study reviews the mechanism of action of anticancer, antiprotozoal, antibacterial and antiviral activities of ALPs, as well as their clinical use.Methods:A literature search was used as the basis of this review.Results:ALPs target lipid rafts and alter phospholipase D and C signalling cascades, which in turn will modulate the PI3K/Akt/mTOR and RAS/RAF/MEK/ERK pathways. By feedback coupling, the SAPK/JNK signalling chain is also affected. These changes lead to a G2/M phase cell cycle arrest and subsequently induce programmed cell death. The available knowledge on inhibition of AKT phosphorylation, mTOR phosphorylation and Raf down-regulation renders ALPs as attractive candidates for modern medical treatment, which is based on individualized diagnosis and therapy. Corresponding to their unusual profile of activities, their side effects result from cholinomimetic activity mainly and focus on the gastrointestinal tract. These aspects together with their bone marrow sparing features render APCs well suited for modern combination therapy. Although the clinical success has been limited in cancer diseases so far, the use of miltefosine against leishmaniosis is leading the way to better understanding their optimized use.Conclusion:Recent synthetic programs generate congeners with the increased therapeutic ratio, liposomal formulations, as well as diapeutic (or theranostic) derivatives with optimized properties. It is anticipated that these innovative modifications will pave the way for the further successful development of ALPs.

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators

“…The two related groups of antitumor agents target cell membranes rather than DNA (Van Blitterswijk and Verheij, 2013). ALPs are metabolically stable, nonmutagenic and versatile drugs derived from lysophosphatidylcholine (Kaleagasioglu et al, 2019;Zaremberg et al, 2019). All agents possess long hydrocarbon chains that slow their catabolism (Van Blitterswijk and Verheij, 2008).…”

“…Finally, the third generation possesses a classic or modified phosphocholine polar moiety and an unsaturated alkyl chain. The best-known representative of this group is erufosine (Kaleagasioglu et al, 2019). An ether linkage to its glycerol backbone characterizes the prototype of ALPs, edelfosine (Kaleagasioglu et al, 2019;Zaremberg et al, 2019).…”

“…The best-known representative of this group is erufosine (Kaleagasioglu et al, 2019). An ether linkage to its glycerol backbone characterizes the prototype of ALPs, edelfosine (Kaleagasioglu et al, 2019;Zaremberg et al, 2019). The first APC generation is represented by miltefosine (hexadecylphosphocholine, HPC), which lacks the glycerol backbone and thus shows a less complex metabolism (Kaleagasioglu et al, 2019;Zaremberg et al, 2019).…”

“…An ether linkage to its glycerol backbone characterizes the prototype of ALPs, edelfosine (Kaleagasioglu et al, 2019;Zaremberg et al, 2019). The first APC generation is represented by miltefosine (hexadecylphosphocholine, HPC), which lacks the glycerol backbone and thus shows a less complex metabolism (Kaleagasioglu et al, 2019;Zaremberg et al, 2019). In order to reduce the acetylcholine-like side effects observed for derivatives with a phosphocholine headgroup, as miltefosine, perifosine contained a piperidine moiety instead of phosphocholine and thus showed less side effects in clinical applications.…”

“…In order to reduce the acetylcholine-like side effects observed for derivatives with a phosphocholine headgroup, as miltefosine, perifosine contained a piperidine moiety instead of phosphocholine and thus showed less side effects in clinical applications. Erufosine represents the most novel generation of APCs, which are characterized by a chain length of 22 carbons and the presence of a single double bond (Fiegl et al, 2008;Konigs et al, 2010;Kaleagasioglu and Berger, 2014;Kaleagasioglu et al, 2019;Zaremberg et al, 2019). At clinical concentrations, APCs disturb cell membranes and hamper their phospholipid turnover as well as lipid-based signal and transduction pathways.…”