Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells
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Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells. / 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.
In: CELL DEATH DIFFER, Vol. 6, No. 8, 01.08.1999, p. 736-44.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells
AU - Grusch, M
AU - Rosenberger, G
AU - Fuhrmann, G
AU - Braun, K
AU - Titscher, B
AU - Szekeres, T
AU - Fritzer-Skekeres, M
AU - Oberhuber, G
AU - Krohn, K
AU - Hengstschlaeger, M
AU - Krupitza, G
AU - Jayaram, H N
PY - 1999/8/1
Y1 - 1999/8/1
N2 - 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.
AB - 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.
KW - Adenocarcinoma
KW - Apoptosis
KW - Cell Division
KW - Dose-Response Relationship, Drug
KW - Enzyme Inhibitors
KW - Female
KW - Humans
KW - IMP Dehydrogenase
KW - Nucleosides
KW - Ovarian Neoplasms
KW - Tumor Cells, Cultured
KW - cdc25 Phosphatases
U2 - 10.1038/sj.cdd.4400546
DO - 10.1038/sj.cdd.4400546
M3 - SCORING: Journal article
C2 - 10467347
VL - 6
SP - 736
EP - 744
JO - CELL DEATH DIFFER
JF - CELL DEATH DIFFER
SN - 1350-9047
IS - 8
ER -