Testing the hypothesis that amphiphilic antineoplastic lipid analogues act through reduction of membrane curvature elastic stress
Testing the hypothesis that amphiphilic antineoplastic lipid analogues act through reduction of membrane curvature elastic stress
The alkyllysophospholipid (ALP) analogues Mitelfosine and Edelfosine are anticancer drugs whose mode of action is still the subject of debate. It is agreed that the primary interaction of these compounds is with cellular membranes. Furthermore, the membrane-associated protein CTP: phosphocholine cytidylyltransferase (CCT) has been proposed as the critical target. We present the evaluation of our hypothesis that ALP analogues disrupt membrane curvature elastic stress and inhibit membrane-associated protein activity (e.g. CCT), ultimately resulting in apoptosis. This hypothesis was tested by evaluating structure-activity relationships of ALPs from the literature. In addition we characterized the lipid typology, cytotoxicity and critical micelle concentration of novel ALP analogues that we synthesized. Overall we find the literature data and our experimental data provide excellent support for the hypothesis, which predicts that the most potent ALP analogues will be type I lipids.
alkylphosphocholines, anticancer, type I lipids, ctp: phosphocholine cytidylyltransferase, curvature elastic stress, alkyllysophospholipids
1371-1386
Dymond, Marcus
0deb02c8-4dec-418b-94ec-98594ed597b7
Attard, George
3219075d-2364-4f00-aeb9-1d90f8cd0d36
Postle, Anthony D.
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
6 November 2008
Dymond, Marcus
0deb02c8-4dec-418b-94ec-98594ed597b7
Attard, George
3219075d-2364-4f00-aeb9-1d90f8cd0d36
Postle, Anthony D.
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
Dymond, Marcus, Attard, George and Postle, Anthony D.
(2008)
Testing the hypothesis that amphiphilic antineoplastic lipid analogues act through reduction of membrane curvature elastic stress.
Journal of the Royal Society Interface, 5 (28), .
(doi:10.1098/rsif.2008.0041).
(PMID:18426775)
Abstract
The alkyllysophospholipid (ALP) analogues Mitelfosine and Edelfosine are anticancer drugs whose mode of action is still the subject of debate. It is agreed that the primary interaction of these compounds is with cellular membranes. Furthermore, the membrane-associated protein CTP: phosphocholine cytidylyltransferase (CCT) has been proposed as the critical target. We present the evaluation of our hypothesis that ALP analogues disrupt membrane curvature elastic stress and inhibit membrane-associated protein activity (e.g. CCT), ultimately resulting in apoptosis. This hypothesis was tested by evaluating structure-activity relationships of ALPs from the literature. In addition we characterized the lipid typology, cytotoxicity and critical micelle concentration of novel ALP analogues that we synthesized. Overall we find the literature data and our experimental data provide excellent support for the hypothesis, which predicts that the most potent ALP analogues will be type I lipids.
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e-pub ahead of print date: 15 April 2008
Published date: 6 November 2008
Keywords:
alkylphosphocholines, anticancer, type I lipids, ctp: phosphocholine cytidylyltransferase, curvature elastic stress, alkyllysophospholipids
Identifiers
Local EPrints ID: 59292
URI: http://eprints.soton.ac.uk/id/eprint/59292
ISSN: 1742-5689
PURE UUID: bca088de-4f1d-46da-9837-66c754a5d224
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Date deposited: 08 Sep 2008
Last modified: 16 Mar 2024 02:44
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Author:
Marcus Dymond
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