The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease.
The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease.
复制标题
DOI：
10.18632/oncotarget.2098
复制
发表时间：
2015-02-20
期刊：
影响因子：
--
通讯作者：
Baiocchi RA
中科院分区：
文献类型：
--
作者：
Patton JT;Lustberg ME;Lozanski G;Garman SL;Towns WH;Drohan CM;Lehman A;Zhang X;Bolon B;Pan L;Kinghorn AD;Grever MR;Lucas DM;Baiocchi RA
EB 病毒驱动的淋巴组织增生性疾病 (EBV-LPD) 患者的治疗选择有限。化学免疫治疗方法通常会导致免疫抑制、致命感染和 EBV 重新激活的风险，因此有必要确定能够提供直接抗肿瘤活性同时保留先天性和适应性宿主免疫监视的药物。 Silvestrol 对多种血液恶性肿瘤具有直接抗肿瘤活性，同时对正常单核细胞的毒性极小。然而，西尔维甾醇对免疫功能的影响尚未被描述。我们利用 EBV-LPD 的体外和体内模型来同时检查西维甾醇对肿瘤和正常免疫功能的影响。我们发现西维甾醇可诱导针对 EBV 转化的淋巴母细胞系 (LCL) 的直接抗肿瘤活性，抑制生长，降低 EBV 致癌基因潜伏膜蛋白 1 的表达，并抑制下游 AKT、STAT1 和 STAT3 信号通路。 Silvestrol 通过保留先天性和 EBV 抗原特异性适应性免疫效应子亚群的扩展，促进有效的间接抗肿瘤作用，这些效应子亚群能够在自体共培养物中有效清除 LCL 肿瘤靶标。在自发性 EBV-LPD 动物模型中，西维甾醇表现出显着的治疗活性，依赖于 CD8 阳性 T 细胞的存在。这些发现证实了西维甾醇具有一种新的免疫保护活性，证明了对 EBV 阳性恶性肿瘤患者进行进一步探索的合理性。
Treatment options for patients with Epstein-Barr Virus-driven lymphoproliferative diseases (EBV-LPD) are limited. Chemo-immunotherapeutic approaches often lead to immune suppression, risk of lethal infection and EBV reactivation, thus it is essential to identify agents that can deliver direct anti-tumor activity while preserving innate and adaptive host immune surveillance. Silvestrol possesses direct anti-tumor activity in multiple hematologic malignancies while causing minimal toxicity to normal mononuclear cells. However, the effects of silvestrol on immune function have not been described. We utilized in vitro and in vivo models of EBV-LPD to simultaneously examine the impact of silvestrol on both tumor and normal immune function. We show that silvestrol induces direct anti-tumor activity against EBV-transformed lymphoblastoid cell lines (LCL), with growth inhibition, decreased expression of the EBV oncogene latent membrane protein-1, and inhibition of the downstream AKT, STAT1 and STAT3 signaling pathways. Silvestrol promoted potent indirect anti-tumor effects by preserving expansion of innate and EBV antigen-specific adaptive immune effector subsets capable of effective clearance of LCL tumor targets in autologous co-cultures. In an animal model of spontaneous EBV-LPD, silvestrol demonstrated significant therapeutic activity dependent on the presence of CD8-positive T-cells. These findings establish a novel immune-sparing activity of silvestrol, justifying further exploration in patients with EBV-positive malignancies.
登录
查看更多内容
影响因子：
28.5
作者：
Alachkar H;Santhanam R;Harb JG;Lucas DM;Oaks JJ;Hickey CJ;Pan L;Kinghorn AD;Caligiuri MA;Perrotti D;Byrd JC;Garzon R;Grever MR;Marcucci G
通讯作者：
Marcucci G
影响因子：
5.2
作者：
Chambers, Jennifer M.;Lindqvist, Lisa M.;Rizzacasa, Mark A.
通讯作者：
Rizzacasa, Mark A.
影响因子：
3.6
作者：
Hwang, BY;Su, BN;Kinghorn, AD
通讯作者：
Kinghorn, AD
影响因子：
20.3
作者：
Gottschalk, S;Edwards, OL;Rooney, CM
通讯作者：
Rooney, CM
影响因子：
11.4
作者：
Gires, O;Kohlhuber, F;Hammerschmidt, W
通讯作者：
Hammerschmidt, W