1. ¹Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan
2. ²Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

Correspondence: Professor Y Yura, Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan. E-mail: yura@dent.osaka-u.ac.jp

Received 2 June 2008; Revised 7 August 2008; Accepted 13 September 2008; Published online 24 October 2008.

Abstract

Combining the use of a chemotherapeutic agent with oncolytic virotherapy is a useful way to increase the efficiency of the treatment of cancer. The effect of the histone diacetylase (HDAC) inhibitor trichostatin A (TSA) on the antitumor activity of a herpes simplex virus type-1 (HSV-1) mutant was examined in oral squamous cell carcinoma (SCC) cells. Immunoblotting analysis and immunoflourescence staining revealed that a cytoplasmic nuclear factor-B (NF-B) component, p65, translocated into the nucleus after infection with ₁34.5 gene-deficient HSV-1 R849, indicating that R849 activated NF-B. TSA induced acetylation of p65 and increased the amount of p65 in the nucleus of oral SCC cells. Treatment of R849-infected cells with TSA also increased the amount of nuclear p65 and binding of NF-B to its DNA-binding site and an NF-B inhibitor SN50 diminished the increase in nuclear p65. In the presence of TSA, the production of virus and the expression of LacZ integrated into R849 and glycoprotein D, but not ICP0, ICP6 and thymidine kinase, were increased. The viability of cells treated with a combination of R849 and TSA was lower than that of those treated with R849 only. After treatment with TSA, expression of the cell cycle kinase inhibitor p21 was upregulated and the cell cycle was arrested at G1. These results indicate that TSA enhanced the replication of the HSV-1 mutant through the activation of NF-B and induced cell cycle arrest at G1 to inhibit cell growth. TSA can be used as an enhancing agent for oncolytic virotherapy for oral SCC with ₁34.5 gene-deficient HSV-1.