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

Elisa Messina, Paola Gazzaniga, Vanna Micheli, Maria Rosaria Guaglianone, Silvia Barbato, Stefania Morrone, Luigi Frati, Anna Maria Aglianó, Alessandro Giacomello

Research output: Contribution to journalArticle

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 μM) caused a decrease of intracellular levels of guanine nucleotides, a G1 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 G1 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.

Original languageEnglish
Pages (from-to)812-817
Number of pages6
JournalInternational Journal of Cancer
Volume108
Issue number6
DOIs
Publication statusPublished - Mar 1 2004

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Keywords

  • Apoptosis
  • IMP-dehydrogenase inhibition
  • Neuroblastoma
  • p53-mediated pathways

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Messina, E., Gazzaniga, P., Micheli, V., Guaglianone, M. R., Barbato, S., Morrone, S., Frati, L., Aglianó, A. M., & Giacomello, A. (2004). Guanine nucleotide depletion triggers cell cycle arrest and apoptosis in human neuroblastoma cell lines. International Journal of Cancer, 108(6), 812-817. https://doi.org/10.1002/ijc.11642