Abstract
Alkylphospholipids (APLs) have elicited great interest as antitumor agents due to their unique mode of action on cell membranes. However, their clinical applications have been limited so far by high hemolytic activity. Recently, cationic prodrugs of erufosine, a most promising APL, have been shown to mediate efficient intracellular gene delivery, while preserving the antiproliferative properties of the parent APL. Here, cationic prodrugs of the two APLs that are currently used in the clinic, miltefosine, and perifosine, are investigated and compared to the erufosine prodrugs. Their synthesis, stability, gene delivery and self-assembly properties, and hemolytic activity are discussed in detail. Finally, the potential of the pro-miltefosine and pro-perifosine compounds ME12 and PE12 in combined antitumor therapy is demonstrated using pUNO1-hTRAIL, a plasmid DNA encoding TRAIL, a member of the TNF superfamily. With these pro-APL compounds, we provide a proof of concept for a new promising strategy for cancer therapy combining gene therapy and APL-based chemotherapy.
Highlights
Alkylphospholipids (APLs) are metabolically stable analogs of lysophosphatidylcholines that constitute a new class of anticancer drugs with antiproliferative properties (de Almeida Pachioni et al, 2013; van Blitterswijk and Verheij, 2013; Markova et al, 2014; Jaffrès et al, 2016; Ríos-Marco et al, 2017)
The action of APLs appears to be specific for tumor cells, and both cellular uptake and APL-induced apoptosis are increased in the malignant state of the cells (Kostadinova et al, 2015)
Miltefosine and perifosine have been evaluated for their selective antitumor activity in phase I and II clinical trials against many types of advanced cancers (Figure 1)
Summary
Alkylphospholipids (APLs) are metabolically stable analogs of lysophosphatidylcholines (lysoPCs) that constitute a new class of anticancer drugs with antiproliferative properties (de Almeida Pachioni et al, 2013; van Blitterswijk and Verheij, 2013; Markova et al, 2014; Jaffrès et al, 2016; Ríos-Marco et al, 2017). Due to their similarity with endogenous phospholipids, it is proposed they target the membrane lipid rafts and interfere with lipid homeostasis, altering lipid-linked signaling and inducing apoptosis.
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