Feng Wen-Hai, Kenney Shannon C
Department of Medicine and Microbiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Cancer Res. 2006 Sep 1;66(17):8762-9. doi: 10.1158/0008-5472.CAN-06-1006.
EBV infection in tumor cells is generally restricted to the latent forms of viral infection. Switching the latent form of viral infection into the lytic form may induce tumor cell death. We have previously reported that certain chemotherapy agents can increase the amount of lytic viral gene expression in EBV-positive tumor cells. In this report, we have explored the potential utility of valproic acid (VPA), an anti-seizure drug that also has strong histone deacetylase inhibitory activity, for activating lytic viral gene expression in EBV-positive tumors. Although VPA treatment alone induced only a modest increase in the level of lytic viral gene expression, it strongly enhanced the ability of chemotherapeutic agents to induce lytic EBV gene expression in EBV-positive epithelial and lymphoid cells in vitro. Furthermore, VPA enhanced cell killing in vitro by chemotherapeutic agents in lymphoblastoid cells and gastric cells (AGS) containing wild-type EBV. In contrast, VPA did not enhance the cytotoxicity of chemotherapy in lymphoblastoid cells containing a lytic-defective (BZLF1-knockout) form of EBV or in EBV-negative AGS cells. Finally, we found that the combination of VPA and chemotherapy was significantly more effective in inhibiting EBV-driven lymphoproliferative disease in severe combined immunodeficient mice than chemotherapy alone. These results suggest that VPA could potentiate the efficacy of chemotherapy for EBV-positive tumors in patients.
肿瘤细胞中的EBV感染通常局限于病毒感染的潜伏形式。将病毒感染的潜伏形式转变为裂解形式可能会诱导肿瘤细胞死亡。我们之前报道过，某些化疗药物可以增加EBV阳性肿瘤细胞中裂解性病毒基因的表达量。在本报告中，我们探究了丙戊酸（VPA）——一种也具有强大组蛋白脱乙酰酶抑制活性的抗癫痫药物——在激活EBV阳性肿瘤中裂解性病毒基因表达方面的潜在效用。尽管单独使用VPA处理仅能使裂解性病毒基因表达水平有适度增加，但它能强烈增强化疗药物在体外诱导EBV阳性上皮细胞和淋巴细胞中EBV裂解基因表达的能力。此外，VPA增强了化疗药物在含有野生型EBV的淋巴母细胞和胃细胞（AGS）中体外杀伤细胞的作用。相比之下，VPA并未增强化疗对含有裂解缺陷型（BZLF1基因敲除）EBV的淋巴母细胞或EBV阴性AGS细胞的细胞毒性。最后，我们发现VPA与化疗联合使用在抑制严重联合免疫缺陷小鼠中EBV驱动的淋巴增殖性疾病方面比单独使用化疗显著更有效。这些结果表明，VPA可以增强化疗对EBV阳性肿瘤患者的疗效。
