Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells

Michael Grusch, Georg Rosenberger, Gerhard Fuhrmann, Katja Braun, Birgit Titscher, Thomas Szekeres, Monika Fritzer-Skekeres, Georg Oberhuber, Karsten Krohn, Markus Hengstschlaeger, Georg Krupitza, Hiremagalur N. Jayaram

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

One of the mechanisms of action of a new oncolytic agent, benzamide riboside (BR) is by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH) which catalyzes the formation of xanthine 5'-monophosphate from inosine 5'-monophosphate and nicotinamide adenine dinucleotide, thereby restricting the biosynthesis of guanylates. In the present study BR (10-20 μM) induced apoptosis in a human ovarian carcinoma N.1 cell line (a monoclonal derivative of its heterogenous parent line HOC-7). This was ascertained by DNA fragmentation, TUNEL assay, [poly(ADP)ribose polymerase]-cleavage and alteration in cell morphology. Apoptosis was accompanied by sustained c-Myc expression, concurrent down-regulation of cdc25A mRNA and protein, and by inhibition of Cdk2 activity. Both Cdk2 and cdc25A are G1 phase specific genes and Cdk2 is the target of Cdc25A. These studies demonstrate that BR exhibits dual mechanisms of action, first by inhibiting IMPDH, and second by inducing apoptosis, which is associated with repression of components of the cell cycle that are downstream of constitutive c-Myc expression.

Original languageEnglish (US)
Pages (from-to)736-744
Number of pages9
JournalCell Death and Differentiation
Volume6
Issue number8
DOIs
StatePublished - Aug 1999

Keywords

  • Apoptosis
  • Benzamide riboside
  • c-myc induction
  • Cdc25A repression
  • Cyclin D1/prad 1 expression
  • IMP dehydrogenase inhibitor

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Grusch, M., Rosenberger, G., Fuhrmann, G., Braun, K., Titscher, B., Szekeres, T., Fritzer-Skekeres, M., Oberhuber, G., Krohn, K., Hengstschlaeger, M., Krupitza, G., & Jayaram, H. N. (1999). Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells. Cell Death and Differentiation, 6(8), 736-744. https://doi.org/10.1038/sj.cdd.4400546