Anticancer mechanisms and clinical application of alkylphospholipids

Biochim Biophys Acta. 2013 Mar;1831(3):663-74. doi: 10.1016/j.bbalip.2012.10.008. Epub 2012 Nov 5.

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.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Endocytosis
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Organophosphates / pharmacology*
  • Organophosphates / therapeutic use
  • Phosphatidylinositol 3-Kinase / genetics
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phospholipid Ethers / pharmacology*
  • Phospholipid Ethers / therapeutic use
  • Phosphorylcholine / analogs & derivatives*
  • Phosphorylcholine / pharmacology
  • Phosphorylcholine / therapeutic use
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quaternary Ammonium Compounds / pharmacology*
  • Quaternary Ammonium Compounds / therapeutic use
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Organophosphates
  • Phosphoinositide-3 Kinase Inhibitors
  • Phospholipid Ethers
  • Quaternary Ammonium Compounds
  • erucylphospho-N,N,N-trimethylpropylammonium
  • Phosphorylcholine
  • erucylphosphocholine
  • edelfosine
  • perifosine
  • miltefosine
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt