Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: A novel method to potentiate natural killer cell tumor cytotoxicity
Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: A novel method to potentiate natural killer cell tumor cytotoxicity
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DOI：
10.1158/0008-5472.can-06-0680
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发表时间：
2006-07-15
期刊：
影响因子：
11.2
通讯作者：
Childs, Richard
中科院分区：
文献类型：
--
作者：
Lundqvist, Andreas;Abrams, Scott I.;Childs, Richard
蛋白酶体抑制剂硼替佐米和组蛋白去乙酰化酶抑制剂缩肽（FK 228）上调肿瘤死亡受体。因此，我们研究了用这些药物预处理恶性细胞是否会增强自然杀伤（NK）介导的肿瘤杀伤。将从健康供体和癌症患者分离的INK细胞在体外扩增，然后在暴露于硼替佐米或缩肽之前和之后测试针对肿瘤细胞系的细胞毒性。在13个肾细胞癌细胞系中的11个（85%）和37个其他癌细胞系中的16个（43%）中，与未处理的肿瘤对照相比，暴露于这些药物显著增加了NK细胞介导的肿瘤溶解（P < 0.001）。此外，从转移性肾细胞癌患者扩增的NK细胞对自体肿瘤细胞的细胞毒性显著更强，与未经处理的肿瘤相比，用硼替佐米或缩酚肽预处理的母鸡。NK细胞致敏的肿瘤表面DR 5 [肿瘤坏死因子相关凋亡诱导配体（TRAIL）-R2; P < 0.05]表达显著增加;相反，MHC I类分子、MIC-A/B、DR 4（TRAIL-R1）和Fas（CD 95）的表面表达没有变化。通过阻断NK细胞上的TRAIL完全消除对NK细胞杀伤的增强的易感性，并且通过阻断肿瘤细胞上的DR 5部分消除对NK细胞杀伤的增强的易感性。这些研究结果表明，药物诱导的致敏TRAIL可以作为一种新的策略，以加强过继输注的NK细胞在癌症患者的抗癌作用。
The proteasome inhibitor, bortezomib, and the histone deacetylase inhibitor, depsipeptide (FK228), up-regulate tumor death receptors. Therefore, we investigated whether pretreatment of malignant cells with these agents would potentiate natural killer (NK)-mediated tumor killing. INK cells isolated from healthy donors and patients with cancer were expanded in vitro and then tested for cytotoxicity against tumor cell lines before and after exposure to bortezomib or depsipeptide. In 11 of 13 (85%) renal cell carcinoma cell lines and in 16 of 37 (43%) other cancer cell lines, exposure to these drugs significantly increased NK cell-mediated tumor lysis compared with untreated tumor controls (P < 0.001). Furthermore, NK cells expanded from patients with metastatic renal cell carcinoma were significantly more cytotoxic against autologous tumor cells v.,hen pretreated with either bortezomib or depsipeptide compared with untreated tumors. Tumors sensitized to NK cell cytotoxicity showed a significant increase in surface expression of DR5 [tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-R2; P < 0.05]; in contrast, surface expression of MHC class I, MIC-A/B, DR4 (TRAIL-R1), and Fas (CD95) did not change. The enhanced susceptibility to INK cell killing was completely abolished by blocking TRAIL on NK cells, and partially abolished by blocking DR5 on tumor cells. These findings show that drug-induced sensitization to TRAIL could be used as a novel strategy to potentiate the anticancer effects of adoptively infused NK cells in patients with cancer.