Document Detail

Lack of ceramide generation and altered sphingolipid composition are associated with drug resistance in human ovarian carcinoma cells.
MedLine Citation:
PMID:  16356169     Owner:  NLM     Status:  MEDLINE    
PTX (Paclitaxel) is an antimitotic agent used in the treatment of a number of major solid tumours, particularly in breast and ovarian cancer. This study was undertaken to gain insight into the molecular alterations producing PTX resistance in ovarian cancer. PTX treatment is able to induce apoptosis in the human ovarian carcinoma cell line, CABA I. PTX-induced apoptosis in CABA I cells was accompanied by an increase in the cellular Cer (ceramide) levels and a decrease in the sphingomyelin levels, due to the activation of sphingomyelinases. The inhibition of acid sphingomyelinase decreased PTX-induced apoptosis. Under the same experimental conditions, PTX had no effect on Cer and sphingomyelin levels in the stable PTX-resistant ovarian carcinoma cell line, CABA-PTX.The acquisition of the PTX-resistant phenotype is accompanied by unique alterations in the complex sphingolipid pattern found on lipid extraction. In the drug-resistant cell line, the levels of sphingomyelin and neutral glycosphingolipids were unchanged compared with the drug-sensitive cell line. The ganglioside pattern in CABA I cells is more complex compared with that of CABA-PTX cells. Specifically, we found that the total ganglioside content in CABA-PTX cells was approximately half of that in CABA I cells, and GM3 ganglioside content was remarkably higher in the drug-resistant cell line. Taken together our findings indicate that: i) Cer generated by acid sphingomyelinase is involved in PTX-induced apoptosis in ovarian carcinoma cells, and PTX-resistant cells are characterized by their lack of increased Cer upon drug treatment, ii) PTX resistance might be correlated with an alteration in metabolic Cer patterns specifically affecting cellular ganglioside composition.
Alessandro Prinetti; Danilo Millimaggi; Sandra D'Ascenzo; Matilda Clarkson; Arianna Bettiga; Vanna Chigorno; Sandro Sonnino; Antonio Pavan; Vincenza Dolo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  395     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-03-27     Completed Date:  2006-04-18     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  311-8     Citation Subset:  IM    
Centre of Excellence for Neurodegenerative Disease, Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milan, 20090 Segrate, Italy.
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MeSH Terms
Antineoplastic Agents, Phytogenic / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Ceramides / biosynthesis*
Drug Resistance, Neoplasm*
Gangliosides / metabolism
Ovarian Neoplasms / metabolism*,  pathology*
Paclitaxel / pharmacology
Sphingolipids / chemistry*,  metabolism*
Sphingomyelin Phosphodiesterase / antagonists & inhibitors
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Ceramides; 0/Gangliosides; 0/Sphingolipids; 10028-17-8/Tritium; 33069-62-4/Paclitaxel; EC Phosphodiesterase

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