title: Anticancer mechanisms and clinical application of alkylphospholipids.
abstract: Synthetic alkylphospholipids (ALPs), such as edelfosine, miltefosine, perifosine, erucylphosphocholine and erufosine, represent a relatively new class of structurally related antitumor agents that act on cell membranes rather than on DNA. They selectively target proliferating (tumor) cells, inducing growth arrest and apoptosis, and are potent sensitizers of conventional chemo- and radiotherapy. ALPs easily insert in the outer leaflet of the plasma membrane and cross the membrane via an ATP-dependent CDC50a-containing 'flippase' complex (in carcinoma cells), or are internalized by lipid raft-dependent endocytosis (in lymphoma/leukemic cells). ALPs resist catabolic degradation, therefore accumulate in the cell and interfere with lipid-dependent survival signaling pathways, notably PI3K-Akt and Raf-Erk1/2, and de novo phospholipid biosynthesis. At the same time, stress pathways (e.g. stress-activated protein kinase/JNK) are activated to promote apoptosis. In many preclinical and clinical studies, perifosine was the most effective ALP, mainly because it inhibits Akt activity potently and consistently, also in vivo. This property is successfully exploited clinically in highly malignant tumors, such as multiple myeloma and neuroblastoma, in which a tyrosine kinase receptor/Akt pathway is amplified. In such cases, perifosine therapy is most effective in combination with conventional anticancer regimens or with rapamycin-type mTOR inhibitors, and may overcome resistance to these agents. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
authors.affiliation: Divisions of Cell Biology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. w.v.blitterswijk@nki.nl
authors.forename: Wim J
authors.initials: WJ
authors.lastname: van Blitterswijk
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D004705:Endocytosis; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010755:Organophosphates / Q000494:pharmacology* / Q000627:therapeutic use; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010742:Phospholipid Ethers / Q000494:pharmacology* / Q000627:therapeutic use; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D010755:Organophosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010742:Phospholipid Ethers; D000644:Quaternary Ammonium Compounds; C472787:erucylphospho-N,N,N-trimethylpropylammonium; D010767:Phosphorylcholine; C075010:erucylphosphocholine; C026659:edelfosine; C105905:perifosine; C039128:miltefosine; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt