Abstract
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 MAPkinase/ ERK proliferative and phosphatidylinositol 3-kinase/ Akt survival pathways and the stimulation of the Stressactivated 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.
Keywords: Anticancer ether lipids, alkylphospholipids, edelfosine, miltefosine, perifosine, erucylphosphocholine, apoptosis, signal transduction
Current Pharmaceutical Design
Title: Anticancer Alkylphospholipids: Mechanisms of Action, Cellular Sensitivity and Resistance, and Clinical Prospects
Volume: 14 Issue: 21
Author(s): Wim J. van Blitterswijk and Marcel Verheij
Affiliation:
Keywords: Anticancer ether lipids, alkylphospholipids, edelfosine, miltefosine, perifosine, erucylphosphocholine, apoptosis, signal transduction
Abstract: 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 MAPkinase/ ERK proliferative and phosphatidylinositol 3-kinase/ Akt survival pathways and the stimulation of the Stressactivated 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.
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Cite this article as:
van Blitterswijk J. Wim and Verheij Marcel, Anticancer Alkylphospholipids: Mechanisms of Action, Cellular Sensitivity and Resistance, and Clinical Prospects, Current Pharmaceutical Design 2008; 14 (21) . https://dx.doi.org/10.2174/138161208785294636
DOI https://dx.doi.org/10.2174/138161208785294636 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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