Document Detail


Expression of P-glycoprotein in HeLa cells confers resistance to ceramide cytotoxicity.
MedLine Citation:
PMID:  21042729     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The role of glucosylceramide synthase (GCS) in regulating ceramide-induced apoptosis has been widely studied. The purpose of this investigation was to evaluate the role of P-glycoprotein (P-gp) in regulating ceramide cytotoxicity by using C6-ceramide. To accomplish this, we employed HeLa cells with conditional expression of the multidrug resistance gene 1/P-gp. HeLa cells expressing P-gp (P-gp/on cells) challenged with [14C]C6-ceramide (6 µM), synthesized 4.5-fold the amount of C6-glucosylceramide (GC) compared to HeLa cells with suppressed expression of P-gp (P-gp/off cells), whereas the generated levels of C6-sphingomyelin were almost equal (33 and 29% of intracellular 14C, respectively). Tamoxifen, a P-gp antagonist, decreased the C6-GC levels from 3.5-1.0% in the P-gp/off and from 17-2.8% of the total lipid 14C levels in the P-gp/on cells. Tamoxifen did not inhibit cell-free C6-GC synthesis in the P-gp/off or P-gp/on homogenates. However, a specific GCS inhibitor, ethylenedioxy-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (ethylenedioxy-P4), blocked synthesis by 90%. In the cytotoxicity assays, the P-gp/off cells were sensitive to C6-ceramide and the P-gp/on cells were resistant. Resistance to C6-ceramide in the P-gp/on cells was reversed by tamoxifen but not by ethylenedioxy-P4. Experiments in another cervical cancer model showed that multidrug-resistant P-gp-rich KB-V1 cells synthesized 3-fold more C6-GC from C6-ceramide than the parental, P-gp-poor KB-3-1 cells, and whereas tamoxifen had no effect on the C6-GC synthesis in the KB-3-1 cells, it inhibited synthesis by 70% in the KB-V1 cells. This study demonstrates that P-gp potentiates C6-ceramide glycosylation and if antagonized augments C6-ceramide sensitivity, both features previously ascribed to GCS. We propose that P-gp can be an effective target for enhancing short-chain ceramide cytotoxicity in the treatment of drug-resistant cancer.
Authors:
Jacqueline V Chapman; Valérie Gouazé-Andersson; Myles C Cabot
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of oncology     Volume:  37     ISSN:  1791-2423     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-02     Completed Date:  2011-02-24     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  1591-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Carcinoma / genetics*,  pathology
Cell Survival
Ceramides / pharmacology*
Cyclosporine / pharmacology
Cytotoxins / pharmacology
Drug Evaluation, Preclinical
Drug Resistance, Neoplasm / drug effects,  genetics*
Female
Gene Expression Regulation, Neoplastic / physiology
HeLa Cells
Humans
P-Glycoprotein / genetics*,  metabolism,  physiology
Tamoxifen / pharmacology
Uterine Cervical Neoplasms / genetics*,  pathology
Verapamil / pharmacology
Grant Support
ID/Acronym/Agency:
CA143755/CA/NCI NIH HHS; GM77391/GM/NIGMS NIH HHS; R21 CA143755/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Ceramides; 0/Cytotoxins; 0/N-(alpha-hydroxyoctadecanoyl)phytosphingosine; 0/P-Glycoprotein; 094ZI81Y45/Tamoxifen; 83HN0GTJ6D/Cyclosporine; CJ0O37KU29/Verapamil

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