Depsipeptide (FR901228) enhances the cytotoxic activity of TRAIL by redistributing TRAIL receptor to membrane lipid rafts.
Depsipeptide (FR901228) enhances the cytotoxic activity of TRAIL by redistributing TRAIL receptor to membrane lipid rafts.
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DOI：
10.1016/j.ymthe.2004.12.008
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发表时间：
2005-04
期刊：
影响因子：
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通讯作者：
R. Vanoosten;Jill M. Moore;Aaron T. Ludwig;T. Griffith
中科院分区：
文献类型：
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作者：
R. Vanoosten;Jill M. Moore;Aaron T. Ludwig;T. Griffith
TRAIL（TNF-相关凋亡诱导配体）在各种肿瘤细胞类型中诱导凋亡，并且作为癌症治疗剂正在研究中。编码全长人TRAIL基因的重组腺病毒（Ad 5-TRAIL）的开发取代了肿瘤抑制疗法中对大量可溶性TRAIL蛋白的需要。然而，Ad 5-TRAIL的全部潜力尚未最大化。组蛋白去乙酰化酶抑制剂缩酚肽（FR 901228）的最新研究表明，它增加了细胞对腺病毒感染的易感性并增强了腺病毒转基因表达。因此，人们开始研究缩肽增强Ad 5-TRAIL对人前列腺肿瘤细胞的细胞毒活性的能力。在体外，缩肽增加柯萨奇-腺病毒受体的表达，导致腺病毒感染和转基因表达增加。此外，在缩肽预处理后，Ad 5-TRAIL对肿瘤细胞的杀伤作用更高。更令人惊讶的是，缩肽还增加了前列腺肿瘤细胞对TRAIL诱导的细胞凋亡的敏感性。对负责增加TRAIL响应性的机制的研究揭示了缩肽处理后膜脂筏中TRAIL-R1和TRAIL-R2的水平增加。这些结果表明缩肽是通过多种机制增强Ad 5-TRAIL活性的有效试剂，允许更有效地使用Ad 5-TRAIL作为抗肿瘤疗法。
TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis in various tumor cell types and is under investigation as a cancer therapeutic. The development of a recombinant adenovirus encoding the full-length human TRAIL gene (Ad5-TRAIL) replaces the need for large quantities of soluble TRAIL protein in tumor suppressive therapies. However, the full potential of Ad5-TRAIL has not yet been maximized. Recent investigation of a histone deacetylase inhibitor, depsipeptide (FR901228), has demonstrated that it increases cellular susceptibility to adenovirus infection and augments adenoviral transgene expression. Thus, studies were initiated to evaluate the ability of depsipeptide to enhance the cytotoxic activity of Ad5-TRAIL against human prostate tumor cells.In vitro, depsipeptide increased expression of coxsackie–adenovirus receptor, leading to increased adenoviral infection and transgene expression. Additionally, tumor cell killing by Ad5-TRAIL was higher following depsipeptide pretreatment. More surprisingly, depsipeptide also increased prostate tumor cell sensitivity to TRAIL-induced apoptosis. Investigation into the mechanism responsible for increased TRAIL responsiveness revealed increased levels of TRAIL-R1 and -R2 in membrane lipid rafts following depsipeptide treatment. These results indicate that depsipeptide is a potent agent for enhancing the activity of Ad5-TRAIL by multiple mechanisms, allowing for a more efficient use of Ad5-TRAIL as an antitumor therapy.