| Lipid rafts and metabolic energy differentially determine uptake of anti-cancer alkylphospholipids in lymphoma versus carcinoma cells. | |
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MedLine Citation:
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PMID: 17803969 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Perifosine is a member of the class of synthetic alkylphospholipids (APLs) and is being evaluated as anti-cancer agent in several clinical trials. These single-chain APLs accumulate in cellular membranes and disturb lipid-dependent signal transduction, ultimately causing apoptosis in a variety of tumor cells. The APL prototype edelfosine was previously found to be endocytosed by S49 mouse lymphoma cells via lipid rafts. An edelfosine-resistant cell variant, S49(AR), was found to be cross-resistant to other APLs, including perifosine. This resistance was due to defective synthesis of the raft constituent sphingomyelin, which abrogated APL cellular uptake. Sensitivity of S49 cells to edelfosine was higher than perifosine, which correlated with a relatively higher uptake. Human KB epidermal carcinoma cells were much more sensitive to APLs than S49 cells. Their much higher APL uptake was highly dependent on intracellular ATP and ambient temperature, and was blocked by chlorpromazine, independent of canonical endocytic pathways. We found no prominent role of lipid rafts for APL uptake in these KB cells; contrary to S49(AR) cells, perifosine-resistant KBr cells display normal sphingomyelin synthesis, whereas APL uptake by the responsive KB cells was insensitive to treatment with methyl-beta-cyclodextrin, a cholesterol-sequestrator and inhibitor of raft-mediated endocytosis. In conclusion, different mechanisms determine APL uptake and consequent apoptotic toxicity in lymphoma versus carcinoma cells. In the latter cells, APL uptake is mainly determined by a raft- and endocytosis-independent process, but metabolic energy-dependent process, possibly by a lipid transporter. |
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Authors:
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Stefan R Vink; Arnold H van der Luit; Jeffrey B Klarenbeek; Marcel Verheij; Wim J van Blitterswijk |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2007-08-03 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 74 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2007 Nov |
Date Detail:
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Created Date: 2007-10-22 Completed Date: 2007-12-27 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1456-65 Citation Subset: IM |
Affiliation:
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Division of Experimental Therapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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metabolism Animals Antineoplastic Agents / pharmacology* Apoptosis Carcinoma, Squamous Cell / metabolism* Cell Line, Tumor Drug Resistance, Neoplasm* Humans KB Cells Lymphoma / metabolism* Membrane Microdomains / metabolism* Mice Phospholipid Ethers / pharmacology* Phospholipids / metabolism Phosphorylcholine / analogs & derivatives*, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/D 21266; 0/Phospholipid Ethers; 0/Phospholipids; 107-73-3/Phosphorylcholine; 56-65-5/Adenosine Triphosphate; 65492-82-2/edelfosine |
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