title: N6-isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation.
abstract: 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.affiliation: Istituto di Endocrinologia e Oncologia Sperimentale. I.E.O.S., CNR, Bari, Italy. chilaez@hotmail.com
authors.forename: Chiara
authors.initials: C
authors.lastname: Laezza
authors.forename: Maria
authors.initials: M
authors.lastname: Notarnicola
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Caruso
authors.forename: Caterina
authors.initials: C
authors.lastname: Messa
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Portella
authors.forename: Laura
authors.initials: L
authors.lastname: Fiorentino
authors.forename: Stefania
authors.initials: S
authors.lastname: Stingo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors*; D007541:Isopentenyladenosine / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D017368:Protein Prenylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051381:Rats; D013961:Thyroid Gland / Q000166:cytology
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D007541:Isopentenyladenosine; D008148:Lovastatin; D051228:Geranyltranstransferase; D008798:Mevalonic Acid