Document Detail


N6-isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation.
MedLine Citation:
PMID:  16507758     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The physiological effects of a variety of N6-substituted adenine and adenosine derivatives called cytokinins have been documented in plants, but information on their occurrence and function in other biological system is limited. Here we investigated the anti-proliferative effect of N6-isopentenyladenosine (i6A), an adenosine and isoprenoid derivative, in a thyroid cell system, FRTL-5 wild-type, and K-ras transformed KiMol cells. Addition of i6A to FRTL-5 cells caused a dose-dependent arrest of the G0-G1 cell phase transition associated with a reduction of cells in the S phase that was much more evident in KiMol cells. I6A arrested tumor cell proliferation by inhibiting farnesyl diphosphate synthase (FPPS) and protein prenylation. Indeed the addition of farnesol reversed these effects and i6A affected protein prenylation, in particular lamin B processing. I6A effect was not mediated by the adenosine receptor but was due to a direct modulation of FPPS enzyme activity as a result of its uptake inside the cells. I6A inhibited FPPS activity more efficaciously in KiMol cells than in normal FRTL-5. Moreover, the i6A anti-proliferative effect was evaluated in vivo in a nude mouse xenograft model, where KiMol cells were implanted subcutaneously. Mice treated with i6A showed a drastic reduction in tumor volume. Our findings indicate that this isoprenoid end product might be used for antineoplastic therapy, an application emulating that of the lovastatin and/or farnesyl-transferase inhibitors
Authors:
Chiara Laezza; Maria Notarnicola; Maria Gabriella Caruso; Caterina Messa; Marco Macchia; Simone Bertini; Filippo Minutolo; Giuseppe Portella; Laura Fiorentino; Stefania Stingo; Maurizio Bifulco
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  20     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-03-01     Completed Date:  2006-04-21     Revised Date:  2012-02-15    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  412-8     Citation Subset:  IM    
Affiliation:
Istituto di Endocrinologia e Oncologia Sperimentale. I.E.O.S., CNR, Bari, Italy. chilaez@hotmail.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology*
Cell Division / drug effects
Cell Line / drug effects
Cell Line, Transformed / drug effects
Drug Screening Assays, Antitumor
Geranyltranstransferase / antagonists & inhibitors*
Isopentenyladenosine / pharmacology*
Lovastatin / pharmacology
Male
Mevalonic Acid / metabolism
Mice
Neoplasm Proteins / antagonists & inhibitors*
Protein Prenylation / drug effects
Protein Processing, Post-Translational / drug effects*
Rats
Thyroid Gland / cytology
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Neoplasm Proteins; 150-97-0/Mevalonic Acid; 75330-75-5/Lovastatin; 7724-76-7/Isopentenyladenosine; EC 2.5.1.10/Geranyltranstransferase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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