Antitumor activities of valproic acid on Epstein-Barr virus-associated T and natural killer lymphoma cells.
Epstein-Barr virus (EBV), which infects B cells, T cells, and natural killer (NK) cells, is associated with multiple lymphoid malignancies. Recently, histone deacetylase (HDAC) inhibitors have been reported to have anticancer effects against various tumor cells. In the present study, we evaluated the killing effect of valproic acid (VPA), which acts as an HDAC inhibitor, on EBV-positive and -negative T and NK lymphoma cells. Treatment of multiple T and NK cell lines (SNT13, SNT16, Jurkat, SNK6, KAI3 and KHYG1) with 0.1-5 mM of VPA inhibited HDAC, increased acetylated histone levels and reduced cell viability. No significant differences were seen between EBV-positive and -negative cell lines. Although VPA induced apoptosis in some T and NK cell lines (SNT16, Jurkat and KHYG1) and cell cycle arrest, it did not induce lytic infection in EBV-positive T or NK cell lines. Because the killing effect of VPA was modest (1 mM VPA reduced cell viability by between 22% and 56%), we tested the effects of the combination of 1 mM of VPA and 0.01 μM of the proteasome inhibitor bortezomib. The combined treated of cells with VPA and bortezomib had an additive killing effect. Finally, we administered VPA to peripheral blood mononuclear cells from three patients with EBV-associated T or NK lymphoproliferative diseases. In these studies, VPA had a greater killing effect against EBV-infected cells than uninfected cells, and the effect was increased when VPA was combined with bortezomib. These results indicate that VPA has antitumor effects on T and NK lymphoma cells and that VPA and bortezomib may have synergistic effects, irrespective of the presence of EBV.
Departments of Virology Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Seiko
S
Iwata
Takashi
T
Saito
Yoshinori
Y
Ito
Maki
M
Kamakura
Kensei
K
Gotoh
Jun-Ichi
J
Kawada
Yukihiro
Y
Nishiyama
Hiroshi
H
Kimura
D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D005260:Female; D004854:Herpesvirus 4, Human / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D008297:Male; D011719:Pyrazines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D014635:Valproic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011719:Pyrazines; D014635:Valproic Acid; D000069286:Bortezomib; D006655:Histone Deacetylases