Inhibition of poly (ADP-ribose) polymerase as a protective effect of nicaraven in ionizing radiation- and ara-C-induced cell death.
BACKGROUND
Nicaraven is a drug used for patients with a subarachnoid hemorrhage. It crosses the blood-brain barrier and has potent antivasospastic and brain-protective effects. While nicaraven scavenges the hydroxyl radical, the mechanism of its protection remains obscure. In addition to the hydroxyl radical scavenging effect, nicaraven also exhibits inhibitory action on poly (ADP-ribose) polymerase (PARP). The mechanism of the pharmacological action of nicaraven has not yet been clarified.


METHODS
Human myeloid HL-525 cells were exposed to ionizing radiation or hydrogen peroxide and the effect of nicaraven on the activation of the Egr-1 promoter was measured. Next, the action of the drug on DNA fragmentation and inhibition of thymidine uptake caused by the genotoxic stimulation of ionizing radiation or cytosine B-D-arabinofuranoside (ara-C) were assessed. Finally, direct inhibition of the PARP enzyme by nicaraven was measured.


RESULTS
Nicaraven did not inhibit the activation of the Egr-1 promoter caused by H2O2 and the activation caused by ionizing radiation. However, the drug repressed DNA fragmentation and increased thymidine uptake dose-dependently. Nicaraven had a direct inhibitory effect on PARP.


CONCLUSIONS
The effect of nicaraven on the Egr-1 promoter was different from that of another free-radical scavenger, N-acetyl cysteine. Nicaraven demonstrated similar protection of the PARP inhibitors including 3-aminobenzamide. Since nicaraven directly inhibits the PARP enzyme, the drug might be useful in oncology as well as in studying tissue-damaging conditions characterized by increased PARP activity.
Watanabe
Michiko
M
Department of Molecular Cell Biology, Institute of DNA Medicine, Center for Medical Sciences, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan. troy@jikei.ac.jp
Akiyama
Nobutake
N
Sekine
Hiroshi
H
Mori
Mariko
M
Manome
Yoshinobu
Y
D000111:Acetylcysteine / Q000494:pharmacology; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000256:Adenoviridae / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003561:Cytarabine / Q000633:toxicity*; D051766:Early Growth Response Protein 1 / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D017930:Genes, Reporter / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020011:Protective Agents / Q000494:pharmacology*; D011839:Radiation, Ionizing; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D013936:Thymidine / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D000964:Antimetabolites, Antineoplastic; D000975:Antioxidants; D001549:Benzamides; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D016166:Free Radical Scavengers; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents; D003561:Cytarabine; D009536:Niacinamide; C025160:3-aminobenzamide; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; C042625:nicaraven; D013936:Thymidine; D000111:Acetylcysteine