Document Detail


P-glycoprotein antagonists confer synergistic sensitivity to short-chain ceramide in human multidrug-resistant cancer cells.
MedLine Citation:
PMID:  21396934     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
P-glycoprotein (P-gp) antagonists inhibit ceramide metabolism at the juncture of glycosylation. The purpose of this study was to test whether targeting P-gp would be a viable alternative to targeting glucosylceramide synthase (GCS) for enhancing ceramide cytotoxicity. A2780 wild-type, and multidrug-resistant 2780AD and NCI/ADR-RES human ovarian cancer cell lines and the cell-permeable ceramide analog, C6-ceramide (C6-cer), were employed. Compared to P-gp-poor A2780 cells, P-gp-rich 2780AD cells converted 3.7-fold more C6-cer to nontoxic C6-glucosylceramide (C6-GC), whereas cell-free GCS activities were equal. 2780AD cells displayed resistance to C6-cer (10 μM) that was reversed by inclusion of the P-gp antagonist tamoxifen (5 μM) but not by inclusion of a GCS inhibitor. Co-administration of C6-cer and P-gp antagonists was also effective in NCI/ADR-RES cells. For example, C6-cer, VX-710 (Biricodar), and cyclosporin A (cyc A) exposure resulted in viabilities of ~90% of control; however, C6-cer/VX-710 and C6-cer/cyc A additions were synergistic and resulted in viabilities of 22% and 17%, respectively. Further, whereas C6-ceramide and cyc A imparted 1.5- and 0-fold increases in caspase 3/7 activity, the combination produced a 3.5-fold increase. Although the upstream elements of cell death have not been elucidated, the novel C6-ceramide/P-gp antagonist combination merits further study and assessment of clinical translational potential.
Authors:
Jacqueline V Chapman; Valérie Gouazé-Andersson; Ramin Karimi; Maria C Messner; Myles C Cabot
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-03-21
Journal Detail:
Title:  Experimental cell research     Volume:  317     ISSN:  1090-2422     ISO Abbreviation:  Exp. Cell Res.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-20     Completed Date:  2011-10-03     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1736-45     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
Affiliation:
John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Hormonal / pharmacology
Antineoplastic Combined Chemotherapy Protocols
Blotting, Western
Ceramides / pharmacology*
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
Drug Synergism
Female
Glucosyltransferases / antagonists & inhibitors,  metabolism
Humans
Ovarian Neoplasms / drug therapy*,  metabolism,  pathology
P-Glycoprotein / antagonists & inhibitors*,  metabolism
Tamoxifen / pharmacology*
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
GM77391/GM/NIGMS NIH HHS; R01 GM077391-04/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Hormonal; 0/Ceramides; 0/P-Glycoprotein; 038753E78J/N-caproylsphingosine; 10540-29-1/Tamoxifen; EC 2.4.1.-/Glucosyltransferases; EC 2.4.1.80/ceramide glucosyltransferase
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