Valproic acid inhibits proliferation of EB virus-infected natural killer cells.
There is no recognized treatment for Epstein-Barr virus (EBV)-associated natural killer (NK) cell lymphoproliferative disorders (LPDs). To determine the possibility of histone deacetylase inhibitors as a therapeutic tool for such disorders, we investigated the anti-proliferative effects of valproic acid (VPA) on two EBV-infected NK cell lines (KAI3 and NKED). VPA inhibited the growth of both lines in a dose- and time-dependent manner by inducing histone hyperacetylation. G1 cell cycle arrest was induced at 24 hours and was associated with increased expression of p21(WAF1), p27(Kip1), and cyclin E and decreased expression of cyclin D2, CDK4, and c-myc. Sub-G1 fractions were not significantly changed at 24 hours, whereas cleaved caspase-3 and cleaved PARP were already detected, and the extrinsic apoptotic pathway, determined by cleaved caspase-8, was activated. Finally, sub-G1 accumulation was increased after 72 hours following stimulation. These findings indicate that VPA might be a therapeutic option for EBV-associated NK-cell LPDs.
Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan. kazfujii@cc.okayama-u.ac.jp
Kazuyasu
K
Fujii
Norihiro
N
Suzuki
Takenobu
T
Yamamoto
Daisuke
D
Suzuki
Keiji
K
Iwatsuki
D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000188:drug therapy / Q000821:virology; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*
D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014635:Valproic Acid