| Ceramide regulates gemcitabine-induced senescence and apoptosis in human pancreatic cancer cell lines. | |
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MedLine Citation:
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PMID: 19531570 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Bioactive sphingolipids are potent intracellular signaling molecules having profound effects on cell death, growth, and differentiation. Pharmacologic manipulation of sphingolipid levels could have a significant effect on the induction of apoptosis by anticancer agents, and thus, improve treatment efficacy. We observed that gemcitabine cannot completely kill AsPc1 and Panc1 human pancreatic cancer cells in culture; even at high concentrations of gemcitabine, 30% to 40% of the cells remain viable. By adding sphingomyelin to the culture medium, gemcitabine-induced cell death increased synergistically to >90%. Panc1 cells that survived high concentrations of gemcitabine had an increase in beta-galactosidase activity, a marker of senescence. The inclusion of sphingomyelin with gemcitabine reduced beta-galactosidase activity, as compared with cells treated with gemcitabine alone. Expression of p21(waf1/cip1) in both cell lines exposed to sphingomyelin, gemcitabine, and gemcitabine + sphingomyelin varied relative to the untreated group. C(8)-ceramide induced both cell death and senescence in a dose-dependent manner. These results indicate that gemcitabine induces senescence in pancreatic cancer cells and that sphingomyelin-enhanced chemosensitivity is achieved through reducing the induction of senescence by redirecting the cell to enter the apoptotic pathway. Ceramide levels seem to be critical to this decision, with cell cycle progression being uninhibited at low ceramide levels, senescence induced at moderate levels, and apoptosis initiated at high levels. Our results provide further evidence that targeting the sphingolipid metabolism is a means of enhancing the efficacy of chemotherapeutic agents. |
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Authors:
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David E Modrak; Evelyn Leon; David M Goldenberg; David V Gold |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S. Date: 2009-06-16 |
Journal Detail:
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Title: Molecular cancer research : MCR Volume: 7 ISSN: 1557-3125 ISO Abbreviation: Mol. Cancer Res. Publication Date: 2009 Jun |
Date Detail:
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Created Date: 2009-06-24 Completed Date: 2009-09-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101150042 Medline TA: Mol Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 890-6 Citation Subset: IM |
Affiliation:
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Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ 07109, USA. dmodrak@gscancer.org |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antimetabolites, Antineoplastic
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pharmacology Antineoplastic Combined Chemotherapy Protocols / pharmacology* Apoptosis / drug effects* Cell Aging / drug effects Cell Cycle / drug effects Cell Cycle Proteins / metabolism Cell Line, Tumor Cell Survival Ceramides / administration & dosage, pharmacology* Deoxycytidine / administration & dosage, analogs & derivatives*, pharmacology Dose-Response Relationship, Drug Drug Synergism Humans Pancreatic Neoplasms / drug therapy*, metabolism, pathology Sphingomyelins / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA096924/CA/NCI NIH HHS; CA123313/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antimetabolites, Antineoplastic; 0/Cell Cycle Proteins; 0/Ceramides; 0/Sphingomyelins; 103882-84-4/gemcitabine; 951-77-9/Deoxycytidine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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