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