N6-isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation.
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
Laezza
Chiara
C
Istituto di Endocrinologia e Oncologia Sperimentale. I.E.O.S., CNR, Bari, Italy. chilaez@hotmail.com
Notarnicola
Maria
M
Caruso
Maria Gabriella
MG
Messa
Caterina
C
Macchia
Marco
M
Bertini
Simone
S
Minutolo
Filippo
F
Portella
Giuseppe
G
Fiorentino
Laura
L
Stingo
Stefania
S
Bifulco
Maurizio
M
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
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D007541:Isopentenyladenosine; D008148:Lovastatin; D051228:Geranyltranstransferase; D008798:Mevalonic Acid