N6-isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation

Di Matola, Tiziana (2006) N6-isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation. [Tesi di dottorato] (Inedito)

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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 I 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 it 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 cells. 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

Tipologia di documento:Tesi di dottorato
Parole chiave:Inibitori farnesil trasferasi; Cellule tiroidee tumorali; Terapia anticancro
Settori scientifico-disciplinari MIUR:Area 06 Scienze mediche > MED/04 PATOLOGIA GENERALE
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Vecchio, Giancarlo
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Rossi, Guido
Stato del full text:Inedito
Data:2006
Numero di pagine:52
Istituzione:Università degli Studi di Napoli Federico II
Dipartimento o Struttura:Biologia e Patologia Cellulare e Molecolare
Tipo di tesi:Dottorato
Stato dell'Eprint:Inedito
Denominazione del dottorato:Oncologia ed Endocrinologia Molecolare
Ciclo di dottorato:XVII
Numero di sistema:2894
Depositato il:02 Settembre 2008
Ultima modifica:04 Febbraio 2009 09:56

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