Anticancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects.
Synthetic anticancer alkylphospholipids (APLs), such as edelfosine, miltefosine and perifosine, are a group of structurally related lipids that act on cellular membranes rather than the DNA. APLs have essentially one long hydrocarbon chain that allows easy partitioning into membrane lipid bilayers, but they resist catabolic degradation. APLs therefore accumulate in cell membranes and can interfere with normal lipid metabolism and lipid-dependent signal transduction. This action, often leading to apoptosis, is most effective in metabolically active, proliferating cells, such as cancer cells, but not in quiescent normal cells. This review describes the general mechanisms of APL cellular uptake and action. Most important for their biological effect are the inhibition of phosphatidylcholine synthesis, the inhibition of the MAP-kinase/ERK proliferative and phosphatidylinositol 3-kinase/ Akt survival pathways and the stimulation of the Stress-activated protein kinase/JNK pathway, which may lead to apoptosis in cancer cells. APLs are most promising in combination with conventional cancer therapies. For example, ALPs increase the cancer cell sensitivity to radiotherapy in vitro and in vivo. We highlight the clinical potential of perifosine, an orally available APL.
van Blitterswijk
Wim J
WJ
Division of Cellular Biochemistry, Department of Radiotherapy, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. w.v.blitterswijk@nki.nl
Verheij
Marcel
M
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology / Q000532:radiotherapy; D010742:Phospholipid Ethers / Q000493:pharmacokinetics / Q000494:pharmacology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; D010767:Phosphorylcholine; C105905:perifosine