Otsuki Akihiro, Patel Ankita, Kasai Kazue, Suzuki Masataka, Kurozumi Kazuhiko, Antonio Chiocca E, Saeki Yoshinaga
Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, Ohio, USA.
Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, Ohio, USA.
Mol Ther. 2008 Sep;16(9):1546-1555. doi: 10.1038/mt.2008.155. Epub 2016 Dec 8.
Replication-conditional (oncolytic) mutants of herpes simplex virus (HSV), are considered promising therapeutic alternatives for human malignancies, and chemotherapeutic adjuvants are increasingly sought to augment their efficacy. Histone deacetylase (HDAC) inhibitors are a new class of antineoplastic agents because of their potent activity in growth arrest, differentiation, and apoptotic death of cancer cells. The ability of the HDAC inhibitors to upregulate exogenous transgene expression and inhibit interferon (IFN) responses prompted our exploration of their use in improving the antitumor efficacy of oncolytic HSV. We discovered that the yield of viral progeny increased significantly when cultured glioma cells were treated with HDAC inhibitors before viral infection. Valproic acid (VPA), a commonly used antiepileptic agent with HDAC inhibitory activity, proved most effective when used to treat glioma cells before viral infection, but not concomitantly with viral infection. Pretreatment with VPA inhibited the induction of several IFN-responsive antiviral genes, augmented the transcriptional level of viral genes, and improved viral propagation, even in the presence of type I IFNs. Moreover, VPA pretreatment improved the propagation and therapeutic efficacy of oncolytic HSV in a human glioma xenograft model in vivo. These findings indicate that HDAC inhibitors can improve the efficacy of tumor virotherapies.
单纯疱疹病毒（HSV）的复制条件性（溶瘤性）突变体被认为是治疗人类恶性肿瘤的有前景的替代疗法，人们越来越多地寻求化疗佐剂来增强其疗效。组蛋白脱乙酰酶（HDAC）抑制剂因其在癌细胞生长停滞、分化和凋亡死亡方面的强大活性而成为一类新型抗肿瘤药物。HDAC抑制剂上调外源转基因表达和抑制干扰素（IFN）反应的能力促使我们探索其在提高溶瘤性HSV抗肿瘤疗效中的应用。我们发现，在病毒感染前用HDAC抑制剂处理培养的胶质瘤细胞时，病毒子代的产量显著增加。丙戊酸（VPA）是一种具有HDAC抑制活性的常用抗癫痫药物，在病毒感染前用于治疗胶质瘤细胞时被证明最有效，但不能与病毒感染同时使用。VPA预处理抑制了几种IFN反应性抗病毒基因的诱导，提高了病毒基因的转录水平，并改善了病毒繁殖，即使在存在I型IFN的情况下也是如此。此外，VPA预处理提高了溶瘤性HSV在体内人胶质瘤异种移植模型中的繁殖和治疗效果。这些发现表明，HDAC抑制剂可以提高肿瘤病毒疗法的疗效。
