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 farnesyltransferase inhibitors.