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

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 res...

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Veröffentlicht in:Cell death and differentiation 1999-08, Vol.6 (8), p.736-744
Hauptverfasser: 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
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container_end_page 744
container_issue 8
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container_title Cell death and differentiation
container_volume 6
creator 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
description 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 microM) 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.
doi_str_mv 10.1038/sj.cdd.4400546
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subjects Adenocarcinoma
Apoptosis - drug effects
benzamide riboside
c-Myc protein
cdc25 Phosphatases - biosynthesis
cdc25 Phosphatases - genetics
Cdc25A protein
Cell Division - drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Female
Humans
IMP Dehydrogenase - antagonists & inhibitors
Nucleosides - metabolism
Nucleosides - pharmacology
Ovarian Neoplasms
Tumor Cells, Cultured
title Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells
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