Division of Hematology & Medical Oncology, Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Republic of Korea; Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Republic of Korea.
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Republic of Korea; Laboratory of Experimental Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Cancer Lett. 2015 Aug 10;364(2):89-97. doi: 10.1016/j.canlet.2015.03.016. Epub 2015 Mar 16.
We investigated the role of the histone deacetylase inhibitor, romidepsin, in Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL), an aggressive non-Hodgkin lymphoma with poor clinical outcomes. We used EBV-positive and EBV-negative DLBCL cell lines and generated two EBV-transfected cell lines, LY7/EBV and U2932/EBV. Romidepsin was cytotoxic to cultured EBV-positive cells via the activation of the caspase cascade. Moreover, in vivo mice xenograft models demonstrated the cytotoxicity of romidepsin to EBV-positive DLBCL cells. Romidepsin induced cytotoxicity via the reduction of LMP1 and c-myc expression in EBV-positive cells. Inhibiting either LMP1 or c-myc using small inhibitory RNAs caused partial cytotoxicity in EBV-positive Farage and U2932/EBV lines. The dual inhibition of LMP1 and c-myc showed a synergistic cytotoxic effect in EBV-positive cells similar in magnitude to that of romidepsin alone. In addition, either double blockade of LMP1 and c-myc activity or romidepsin single treatment activated EBV lytic cycle in EBV-positive cells. In conclusion, romidepsin exerts strong anti-tumor activity in EBV-positive DLBCL via the inhibition of both LMP1 and c-myc. Our findings indicate that romidepsin might be a promising treatment for EBV-positive DLBCL.
我们研究了组蛋白去乙酰化酶抑制剂罗米地辛在 EBV 阳性弥漫性大 B 细胞淋巴瘤（DLBCL）中的作用，EBV 阳性 DLBCL 是一种侵袭性非霍奇金淋巴瘤，临床预后较差。我们使用 EBV 阳性和 EBV 阴性 DLBCL 细胞系，并生成了两个 EBV 转染细胞系，LY7/EBV 和 U2932/EBV。罗米地辛通过激活半胱天冬酶级联反应对培养的 EBV 阳性细胞具有细胞毒性。此外，体内小鼠异种移植模型证明了罗米地辛对 EBV 阳性 DLBCL 细胞的细胞毒性。罗米地辛通过降低 EBV 阳性细胞中的 LMP1 和 c-myc 表达诱导细胞毒性。使用小干扰 RNA 抑制 LMP1 或 c-myc 可导致 EBV 阳性 Farage 和 U2932/EBV 系部分细胞毒性。LMP1 和 c-myc 的双重抑制在 EBV 阳性细胞中显示出与罗米地辛单独作用相似的协同细胞毒性效应。此外，LMP1 和 c-myc 活性的双重阻断或罗米地辛单一处理均可激活 EBV 阳性细胞中的 EBV 裂解周期。总之，罗米地辛通过抑制 LMP1 和 c-myc 对 EBV 阳性 DLBCL 发挥强大的抗肿瘤活性。我们的研究结果表明，罗米地辛可能是 EBV 阳性 DLBCL 的一种有前途的治疗方法。
