Mycophenolic acid (MPA) specifically inhibits inosine-5'-monophosphate dehydrogenase, the first committed step toward GMP biosynthesis. In its morpholinoethyl ester prodrug form it is one of the most promising immunosuppressive drugs recently developed. The aim of the present study was to investigate the in vitro effects of MPA, at concentrations readily attainable during immunosuppressive therapy, on 3 human neuroblastoma cell lines (LAN5, SHEP and IMR32). Mycophenolic acid (0.1-10 muM) caused a decrease of intracellular levels of guanine nucleotides, a G(1) arrest and a time- and dose-dependent death by apoptosis. These effects, associated with an up-regulation of p53, p21 and bax, a shuttling of p53 protein into the nucleus and a down-regulation of bcl-2, survivin and p27 protein, were reversed by the simultaneous addition of guanine or guanosine and were more evident using nondialysed serum containing hypoxanthine. These results suggest that in neuroblastoma cell lines clinically attainable concentrations of mycophenolic acid deplete guanine nucleotide pools triggering G(1) arrest and apoptosis through p53-mediated pathways, indicating a potential role of its morpholinoethyl ester pro-drug in the management of patients with neuroectodermal tumors. (C) 2003 Wiley-Liss, Inc.

Guanine nucleotide depletion triggers cell cycle arrest and apoptosis in human neuroblastoma cell lines / Messina, Elisa; Gazzaniga, Paola; Vanna, Micheli; Maria Rosaria, Guaglianone; Silvia, Barbato; Morrone, Stefania; Frati, Luigi; Agliano', Anna Maria; Giacomello, Alessandro. - In: INTERNATIONAL JOURNAL OF CANCER. - ISSN 0020-7136. - STAMPA. - 108:6(2004), pp. 812-817. [10.1002/ijc.11642]

Guanine nucleotide depletion triggers cell cycle arrest and apoptosis in human neuroblastoma cell lines

MESSINA, ELISA;GAZZANIGA, PAOLA;MORRONE, Stefania;FRATI, Luigi;AGLIANO', Anna Maria;GIACOMELLO, Alessandro
2004

Abstract

Mycophenolic acid (MPA) specifically inhibits inosine-5'-monophosphate dehydrogenase, the first committed step toward GMP biosynthesis. In its morpholinoethyl ester prodrug form it is one of the most promising immunosuppressive drugs recently developed. The aim of the present study was to investigate the in vitro effects of MPA, at concentrations readily attainable during immunosuppressive therapy, on 3 human neuroblastoma cell lines (LAN5, SHEP and IMR32). Mycophenolic acid (0.1-10 muM) caused a decrease of intracellular levels of guanine nucleotides, a G(1) arrest and a time- and dose-dependent death by apoptosis. These effects, associated with an up-regulation of p53, p21 and bax, a shuttling of p53 protein into the nucleus and a down-regulation of bcl-2, survivin and p27 protein, were reversed by the simultaneous addition of guanine or guanosine and were more evident using nondialysed serum containing hypoxanthine. These results suggest that in neuroblastoma cell lines clinically attainable concentrations of mycophenolic acid deplete guanine nucleotide pools triggering G(1) arrest and apoptosis through p53-mediated pathways, indicating a potential role of its morpholinoethyl ester pro-drug in the management of patients with neuroectodermal tumors. (C) 2003 Wiley-Liss, Inc.
2004
apoptosis; imp-dehydrogenase inhibition; neuroblastoma; p53-mediated pathways
01 Pubblicazione su rivista::01a Articolo in rivista
Guanine nucleotide depletion triggers cell cycle arrest and apoptosis in human neuroblastoma cell lines / Messina, Elisa; Gazzaniga, Paola; Vanna, Micheli; Maria Rosaria, Guaglianone; Silvia, Barbato; Morrone, Stefania; Frati, Luigi; Agliano', Anna Maria; Giacomello, Alessandro. - In: INTERNATIONAL JOURNAL OF CANCER. - ISSN 0020-7136. - STAMPA. - 108:6(2004), pp. 812-817. [10.1002/ijc.11642]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/232304
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