Suppressive effect of PARP-1 inhibitor on JC virus replication in vitro.
The incidence of progressive multifocal leukoencephalopathy (PML) has increased due to the AIDS pandemic, hematological malignancies, and immunosuppressive therapies. Recently, the number of cases of monoclonal antibody-associated PML has increased in patients treated with immunomodulatory drugs such as natalizumab. However, no common consensus regarding PML therapy has been reached in clinical studies. In order to examine the suppression of JC virus (JCV) replication by 3-aminobenzamide (3-AB), a representative PARP-1 inhibitor, a DNA replication assay was carried out using the neuroblastoma cell line IMR-32 and IMR-adapted JCV. The suppression of JCV propagation by 3-AB was also examined using JCI cells, which are a carrier culture producing continuously high JCV titers. The results indicated that PARP-1 inhibitors, such as 3-aminobenzamide (3-AB), suppress JCV replication and propagation significantly in vitro, as judged by DNA replication assay, hemagglutination, and real-time PCR analysis. It has been also shown that 3-AB reduced PARP-1 activity in IMR-32 cells. According to the results of the MTT assay, the enzyme activity of 3-AB-treated cells was slightly lower than that of DMSO-treated cells. However, the significant suppression of JCV propagation is not related to the slight decrease in cell growth. To our knowledge, this is the first report that PARP-1 inhibitor suppresses the replication of JCV significantly in neuroblastoma cell lines via the reduction of PARP-1 activity. Thus, PARP-1 inhibitors also may be a novel therapeutic drug for PML.
Department of Microbiology, Kobe Institute of Health, Chuo-ku, Kobe, Japan. s-nuku@gj8.so-net.ne.jp
Souichi
S
Nukuzuma
Masanori
M
Kameoka
Shigeki
S
Sugiura
Kazuo
K
Nakamichi
Chiyoko
C
Nukuzuma
Tsutomu
T
Takegami
D000998:Antiviral Agents / Q000378:metabolism*; D001549:Benzamides / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D007577:JC Virus / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000821:virology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013194:Staining and Labeling; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication
D000998:Antiviral Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; C025160:3-aminobenzamide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C022616:thiazolyl blue