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.
Export Options
About this article
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 |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
The Dark Side of Stem Cells: Triggering Cancer Progression by Cell Fusion
Current Molecular Medicine Progress in Drug Treatment of Cerebral Edema
Mini-Reviews in Medicinal Chemistry Heparanase: Structure, Biological Functions, and Inhibition by Heparin-Derived Mimetics of Heparan Sulfate
Current Pharmaceutical Design Towards Drug Discovery for Brain Tumours: Interaction of Kinins and Tumours at the Blood Brain Barrier Interface
Recent Patents on CNS Drug Discovery (Discontinued) Hyperpolarized 13Carbon MR
Current Pharmaceutical Biotechnology Novel Tri-substituted Thiazoles Bearing Piperazine Ring: Synthesis and Evaluation of their Anticancer Activity
Letters in Drug Design & Discovery Endocannabinoid System in Neurological Disorders
Recent Patents on CNS Drug Discovery (Discontinued) Synthesis and Biological Evaluation of Novel 2-imino-4-thiazolidinones as Potential Antitumor Agents for Glioblastoma
Medicinal Chemistry To Be-et, or Not to Be-et, That is the Question: The Role(s) of Nitrate and Nitrite in Health and Illness
Reviews on Recent Clinical Trials Temozolomide: An Update on Pharmacological Strategies to Increase its Antitumour Activity
Medicinal Chemistry Reviews - Online (Discontinued) Molecular Biology of Nucleoside Transporters and their Distributions and Functions in the Brain
Current Topics in Medicinal Chemistry Nanoparticle-based Cerebral Drug-Delivery Systems and Antiangiogenic Approach in Gliomas Treatment
Recent Patents on Nanotechnology Drug Metabolism and Transport Under Hypoxia
Current Drug Metabolism High Expression of miR-483-5p Predicts Chemotherapy Resistance in Epithelial Ovarian Cancer
MicroRNA Multifunctional Nanoparticles, Nanocages and Degradable Polymers as a Potential Novel Generation of Non-Invasive Molecular and Cellular Imaging Systems
Recent Patents on Nanotechnology Cancer Stem Cells in Pediatric Brain Tumors
Current Stem Cell Research & Therapy The Role of miR-129-5p in Cancer: A Novel Therapeutic Target
Current Molecular Pharmacology Recent Evidence of the Regulatory Role of PPARs in Neural Stem Cells and Their Underlying Mechanisms for Neuroprotective Effects
Current Stem Cell Research & Therapy Telomeric Repeat Containing RNA (TERRA): Aging and Cancer
CNS & Neurological Disorders - Drug Targets Targeting Hypoxia for Sensitization of Tumors to Radio- and Chemotherapy
Current Cancer Drug Targets