Enhancement of Ad5-TRAIL cytotoxicity against renal cell carcinoma with histone deacetylase inhibitors
Enhancement of Ad5-TRAIL cytotoxicity against renal cell carcinoma with histone deacetylase inhibitors
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DOI：
10.1038/sj.cgt.7700939
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发表时间：
2006-06-01
影响因子：
6.4
通讯作者：
Griffith, T. S.
中科院分区：
文献类型：
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作者：
VanOosten, R. L.;Earel, J. K., Jr.;Griffith, T. S.
肾细胞癌（RCC）今年在美国将导致超过12000人死亡。由于对播散性肾细胞癌缺乏有效的治疗，刺激了对包括免疫策略在内的新治疗方法的探索，但不良的治疗反应和明显的毒性限制了它们的使用。肿瘤坏死因子（TNF）家族成员肿瘤坏死因子相关凋亡诱导配体（TRAIL）/Apo-2L在各种肿瘤细胞类型中诱导凋亡，同时对正常细胞几乎没有细胞毒性。在这项研究中，我们研究了重组腺病毒编码人TNFSF 10（Ad 5-TRAIL），单独和与组蛋白去乙酰化酶抑制剂（HDACi）的面板组合，对TRAIL/Apo-2L耐药RCC线786-O和正常人肾近端小管上皮细胞（RPTEC）的杀肿瘤潜力。Ad 5-TRAIL不能单独在786-O或RPTEC中诱导凋亡;然而，当Ad 5-TRAIL与HDAC抑制剂组合时，发生肿瘤细胞凋亡。除了与阿司他丁A组合时，RPTEC对HDACi的Ad 5-TRAIL不敏感。在786- 0中，HDAC抑制诱导CAR表达，允许增加腺病毒感染和转基因表达。它还诱导TRAIL-R2的表达，加速死亡诱导信号复合物的形成，并增强caspase-8的激活。我们的研究结果证明了Ad 5-TRAIL与HDACi组合对RCC的效用，并从机制上定义了这种组合如何调节RCC对TRAIL/Apo-2L和腺病毒感染的敏感性。
Renal cell carcinoma (RCC) will cause greater than 12 000 deaths in the United States this year. The lack of effective therapy for disseminated RCC has stimulated the search for novel treatments including immunotherapeutic strategies, but poor therapeutic responses and marked toxicity have limited their use. The tumor necrosis factor (TNF) family member TNF-related apoptosis-inducing ligand (TRAIL)/Apo-2L induces apoptosis in various tumor cell types, while having little cytotoxicity against normal cells. In this study, we investigated the tumoricidal potential of a recombinant adenovirus encoding human TNFSF10 (Ad5-TRAIL), alone and in combination with a panel of histone deacetylase inhibitors (HDACi), against the TRAIL/Apo-2L-resistant RCC line 786-O and normal human renal proximal tubule epithelial cells (RPTEC). Ad5-TRAIL was unable to induce apoptosis in either 786-O or RPTEC alone; however, tumor cell apoptosis occurred when Ad5-TRAIL was combined with HDAC inhibition. Except when combined with trichostatin A, RPTEC were not sensitized to Ad5-TRAIL by HDACi. In 786-O, HDAC inhibition induced CAR expression, permitting increased adenoviral infection and transgene expression. It also induced TRAIL-R2 expression, accelerated the death-inducing signaling complex formation and enhanced caspase-8 activation. Our results demonstrate the utility of combining Ad5-TRAIL with HDACi against RCC, and mechanistically define how this combination modulates RCC sensitivity to TRAIL/Apo-2L and adenoviral infection.