TRAIL作用机制及其在肿瘤治疗中的研究

肿瘤坏死因子相关凋亡诱导配体(TRAIL)具有特异性抗肿瘤活性,可通过死亡受体途径及转录因子途径发挥诱导肿瘤细胞凋亡作用.而正常细胞则通过诱骗受体、FLIP及凋亡抑制蛋白来逃逸TRAIL诱导的凋亡.TRAIL与化疗药物、基因治疗联合应用能明显提高肿瘤治疗的靶向性,同时还可以逆转肿瘤细胞对TRAIL的抵抗现象.因此TRAIL作为新型抗肿瘤药物有望应用于临床治疗.     

TRAIL诱导肿瘤细胞凋亡机制研究进展

肿瘤坏死因子相关凋亡诱导配体(TRAIL)与死亡受体结合后,可启动凋亡信号转导.在产生一系列凋亡分子的同时,胞内抗凋亡分子也被诱导产生,但单一因素在TRAIL凋亡信号调控网络中并不起决定作用,而是多因素制衡的一个动态过程决定细胞生死.了解TRAIL通路的精确调控机制及肿瘤的遗传背景,对于研究TRAIL在肿瘤治疗中的应用具有决定性作用.现综述近年来TRAIL诱导肿瘤细胞凋亡胞内机制的研究进展.     

TRAIL的抗肿瘤机制及其应用

目的:总结国内外关于TRAIL的抗肿瘤机制及应用的研究进展.方法:应用MEDLINE及CNKI期刊全文数据库系统,以"TRAIL、机制和治疗"等为关键词,检索2000-2010年的相关文献.纳入标准:1)TRAIL的结构及受体;2)TRAIL的作用机制;3)TRAIL的应用及临床试验.根据纳入标准,纳入分析23篇文献.结果:TRAIL在TNF家族中最显著的特征是对肿瘤细胞和转化细胞具有选择性的凋亡诱导作用,而对正常的组织和细胞不具有明显的毒性反应,并且与其他试剂联合应用具有协同抗肿瘤作用.结论:相对于化疗药物的毒副反应,TRAIL的独特优势为其在肿瘤治疗中奠定了良好基础,可以为目前的肿瘤治疗提供更有效,更安全的新方法.     

TRAIL及其受体与肿瘤治疗

TRAIL是肿瘤坏死因子超家族的新成员,能够特异性诱导肿瘤细胞、转化细胞和病毒感染细胞的凋亡,而正常细胞则可逃逸其杀伤作用,是一种极具潜力的新型广谱抗肿瘤药物.现综述近年来有关TRAIL及其受体在肿瘤治疗中的研究进展.     

TRAIL基因原核表达载体的构建、表达与抗体制备

目的:获取抗肿瘤坏死因子相关凋亡诱导配体(TRAIL)抗体.方法:利用PCR技术和基因重组技术将TRAIL基因构建于原核表达载体pPreTMH-Tb中,经酶切、测序鉴定证实构建完全正确后,通过IPTG诱导在大肠杆菌DH-5α中获得表达,并将TRAIL蛋白免疫家兔,通过Dot blot及Western blot检测抗TRAIL抗体的产生.结果:成功构建TRAIL基因原核表达载体,并在大肠杆菌DH-5α中获得表达,TRAIL蛋白表达量占菌体蛋白质总量的11.8%,Dot blot及Western blot检测证实获得了抗TRAIL抗体.结论:成功制备抗TRAIL抗体,这为TRAIL在真核细胞水平研究奠定了实验基础.     

增强TRAIL诱导肿瘤细胞凋亡的研究进展

虽然肿瘤坏死因子相关的凋亡诱导配体(TRAIL)已被证明是一个强有力而且相对安全的凋亡诱导因子,但近年来有许多研究表明,某些肿瘤细胞对TRAIL产生了耐受.也有越来越多的证据表明,TRAIL与其他的药物合用能够达到理想诱导肿瘤细胞凋亡的效果.     

TRAlL与TRAIL受体

TRAIL/TRAIL-R是TNF超家族的一个新亚群,TRAIL可引起肿瘤细胞的凋亡,但不引起正常细胞凋亡.目前TRAIL已发现五种受体:DR4、DR5、DcR1、DcR2、OPG,各具有不同的生物活性.本文就TRAIL及其受体的结构、功能和其机制作一综述.     

基于TRAIL联合治疗的信号通路及协同作用机制研究进展

肿瘤坏死因子相关凋亡配体(TRAIL),属于肿瘤坏死因子超家族成员,因其能特异性结合受体诱导肿瘤细胞凋亡,且对正常细胞没有明显损伤,使其成为一种极具发展潜能的抗肿瘤治疗药物.文献报道称以TRAIL为基础的多药联合治疗具有协同作用,可增强TRAIL受体靶向治疗的疗效.文章就以TRAIL为基础多药联合治疗的信号通路及协同作用机制作一综述.     

以TRAIL为靶点的肿瘤生物治疗研究

TRAIL是TNF家族的新成员，目前已经确认TRAIL有两类受体：死亡受体及“诱骗”受体，其中TRAIL通过与死亡受体结合而诱导靶细胞凋亡，这种凋亡任用具有选择性。TRAIL可以大量、快速地杀伤肿瘤细胞，而人体的正常细胞对TRAIL诱导的凋亡耐受，这一特性为肿瘤的治疗提供新的靶点。本文就TRAIL及其受体，TRAIL诱导凋亡的机制以及影响凋亡的因素和途径，以TRAIL为靶点的肿瘤治疗的研究现状作一全面综述，为肿瘤生物治疗提供新的方法和途径。     

TRAIL联合低剂量顺铂对食管癌EC9706细胞增殖的影响

目的 探讨肿瘤坏死因子相关凋亡诱导配体(TRAIL)联合低剂量顺铂(DDP)对食管癌EC9706细胞增殖的影响.方法 单用DDP和单用TRAIL作用于EC9706细胞24、48、72 h后,利用MTT法检测各处理因素对EC9706细胞增殖的影响;TRAIL联合低剂量DDP作用48 h后,利用MTT法检测各处理因素对EC9706细胞增殖的影响.结果 随着单用DDP和单用TRAIL浓度的提高,作用时间的延长,其对EC9706细胞的抑制作用增强.TRAIL与低剂量DDP联用可明显抑制EC9706细胞的增殖,与单用DDP或单用TRAIL相比,细胞存活率显著降低;联合DDP组和DDP+TRAIL组细胞增殖率均随着DDP浓度的增加而下降.结论 TRAIL与低剂量DDP联合应用,可以抑制食管癌EC9706细胞的增殖,TRAIL能增强食管癌细胞对DDP的敏感性.     

TRAIL receptor-targeted therapy

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines. Based on its ability to induce apoptosis selectively in a wide variety of cancer cell lines and human tumor xenografts, TRAIL has been in drug development as a potential biological agent for cancer therapy. A variety of chemotherapy agents have been shown to enhance the cytotoxic effects of TRAIL. The potential benefits of TRAIL as an anticancer therapy have been further indicated by its ability to enhance the efficacy of radiotherapy. Preclinical studies have shown the potential use of agonistic monoclonal antibodies that selectively bind TRAIL death receptors for cancer therapy. This review provides an overview of TRAIL receptor-mediated apoptosis of tumor cells, with TRAIL or agonistic monoclonal antibodies only or with chemotherapy drugs. Treatment of tumor xenografts with these ligands, alone or in combination with chemotherapy or radiation, are discussed along with preliminary information about early clinical trials. Additional clinical trials with TRAIL receptor ligands in combination treatment regimens are required to determine their potential for targeted therapy of cancer.     

阿霉素联合TRAIL对人肝癌细胞增殖与TRAIL受体表达的影响

目的 探讨阿霉素联合肿瘤坏死因子相关凋亡诱导配体（TRAIL）对肝癌细胞HepG2和SMMC-7721增殖及TRAIL受体表达的影响。方法 采用MTT法分别检测阿霉素、TRAIL及低浓度阿霉素联合TRAIL处理HepG2和SMMC-7721细胞的生长抑制率;RT-PCR和Western blotting分别检测阿霉素作用前后HepG2和SMMC-7721细胞TRAIL受体DR4、DR5的mRNA和蛋白表达水平。结果 3种浓度阿霉素（0.86、8.6、86μmol／L）作用24h后,对HepG2和SMMC-7721细胞的生长抑制率分别为（8.84±0.44）％和（8.67±1.22）％、（24.12±1.11）％和（25.39±2.26）％、（64.55±4.05）％和（66.2±3.74）％,呈浓度依赖性,不同浓度组之间差异均有统计学意义（P＜0.05）。4种浓度TRAIL（10、100、500、1000ng／ml）作用24h后,对HepG2和SMMC 7721细胞的生长抑制率分别为（5.83±0.25）％和（5.66±0.56）％、（9.60±1.38）％和（8.96±1.13）％、（11.87±1.43）％和（12.11±1.84）％、（15.12±3.84）％和（16.16±1.41）％,其他3种浓度分别与10ng／ml TRAIL比较,差异均有统计学意义（P＜0.01）。低浓度阿霉素联合TRAIL作用于HepG2和SMMC-7721细胞,低浓度阿霉素能够增加HepG2和SMMC-7721细胞对TRAIL治疗的敏感性,并且随着时间的延长和TRAIL浓度的增加,细胞抑制率逐渐增加,呈时间 效应和剂量 效应关系;无论在mRNA还是蛋白水平,阿霉素处理后HepG2细胞死亡受体DR4、DR5的表达水平较未处理组显著增加;在SMMC-7721细胞,阿霉素处理后,DR5的表达水平显著增加,而DR4的表达水平与阿霉素未处理组相似。结论 低浓度阿霉素能够增加肝癌细胞对TRAIL治疗的敏感性,其机制可能是阿霉素增加死亡受体特别是DR5的表达水平,从而诱导细胞凋亡增加,TRAIL在肝癌治疗方面存在潜在的临床应用价值。     

TRAIL系统与卵巢肿瘤

肿瘤坏死因子相关凋亡诱导配体(TRAIL)是新近发现的肿瘤坏死因子家族成员,它可以选择性杀伤肿瘤细胞及转化细胞,对正常组织细胞没有杀伤作用,而且可以增强放化疗的敏感性,这些特点使其在卵巢肿瘤治疗中有着广泛的应用前景.现就TRAIL系统与卵巢肿瘤的研究作一综述.     

TRAIL受体在人肝细胞癌中的表达及TRAIL诱导的肝癌细胞凋亡

目的 研究了RAIL受体在肝癌组织及肝癌细胞中的表达,探讨肿瘤坏死因子相关凋亡诱导配体(TRAIL)及其受体在肝癌细胞凋亡诱导中的作用。 方法 应用RT-PCR法和免疫组化方法检测肝癌组织及细胞系SK-Hepl中TRAIL受体的表达,并以TRAIL蛋白和γ-干扰素作用于SK-Hepl细胞,观察其对细胞的凋亡诱导作用。 结果 在肝癌组织及肝癌SK-Hepl细胞系中均可检测到TRAIL受体,其中,死亡受体DR4、DR5在肝癌、癌旁组织以及SK-Hepl肝癌细胞系中均呈高表达,而诱骗受体DcR1及DcR2呈低表达,明显低于正常组织。TRAIL对肝癌细胞有凋亡诱导作用,与干扰素的协同时,其作用明显增强。 结论 肝癌组织中存在着TRAIL受体的表达,TRAIL可诱导肝癌SK-Hepl细胞系凋亡,其作用与DR4、DR5的高表达有关。     

Targeting Apo2L/TRAIL receptors by soluble Apo2L/TRAIL

The early observation that Apo2L/TRAIL preferentially triggers apoptosis in tumor cells over normal cells highlighted its potential as a candidate therapeutic in cancer. Since its identification in the mid-1990s, our increased understanding of Apo2L/TRAIL and Apo2L/TRAIL receptor signaling has led to the development of several agonists designed to promote tumor cell apoptosis through death receptor engagement. Recombinant human Apo2L/TRAIL/dulanermin is unique in that it is the only agonist which binds both Apo2L/TRAIL death receptors. In pre-clinical studies dulanermin demonstrates broad spectrum anti-tumor activity and the ability to cooperate with multiple conventional and targeted therapies. Results from early stage clinical trials indicate that dulanermin is well tolerated and shows some evidence of clinical activity. Not all tumors are likely to be equally sensitive to apoptosis induction by Apo2L/TRAIL. Therefore, an increased understanding of the regulation of Apo2L/TRAIL signaling should aid in the identification of molecular signatures that define a patient population likely to respond. In this review, current knowledge and new insights about Apo2L/TRAIL signaling is discussed with the focus on the development of Apo2L/TRAIL as a cancer therapeutic.     

DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer

Current treatment modalities for pancreatic carcinoma afford only modest survival benefits. TRAIL, as a potent and specific inducer of apoptosis in cancer cells, would be a promising new treatment option. However, since not all pancreatic cancer cells respond to TRAIL, further improvements and optimizations are still needed. One strategy to improve the effectiveness of TRAIL-based therapies is to specifically target one of the 2 cell death inducing TRAIL-receptors, TRAIL-R1 or TRAIL-R2 to overcome resistance. To this end, we designed constructs expressing soluble TRAIL (sTRAIL) variants that were rendered specific for either TRAIL-R1 or TRAIL-R2 by amino acid changes in the TRAIL ectodomain. When we expressed these constructs, including wild-type sTRAIL (sTRAIL^wt), TRAIL-R1 (sTRAIL^DR4) and TRAIL-R2 (sTRAIL^DR5) specific variants, in 293 producer cells we found all to be readily expressed and secreted into the supernatant. These supernatants were subsequently transferred onto target cancer cells and apoptosis measured. We found that the TRAIL-R1 specific variant had higher apoptosis-inducing activity in human pancreatic carcinoma Colo357 cells as well as PancTu1 cells that were additionally sensitized by targeting of XIAP. Finally, we tested TRAIL-R1 specific recombinant TRAIL protein (rTRAIL^DR4) on Colo357 xenografts in nude mice and found them to be more efficacious than rTRAIL^wt. Our results demonstrate the benefits of synthetic biological approaches and show that TRAIL-R1 specific variants can potentially enhance the therapeutic efficacy of TRAIL-based therapies in pancreatic cancer, suggesting that they can possibly become part of individualized and tumor specific combination treatments in the future.