肿瘤坏死因子相关凋亡诱导配体在消化系统肿瘤治疗中的研究进展

肿瘤坏死因子相关凋亡诱导配体（TRAIL）可通过特异性识别肿瘤细胞死亡受体而诱导并启动多种凋亡机制,发挥抑制肿瘤的增殖、浸润、转移的作用,但TRAIL对食管癌、胃癌、大肠癌等消化系统恶性肿瘤治疗并不敏感。TRAIL可通过联合使用某些小分子化合物,或通过调节凋亡相关蛋白的表达等来提高其抑癌的能力,然而其具体作用机制尚不清楚。就肿瘤坏死因子相关凋亡诱导配体在消化系统肿瘤治疗中的研究进展进行综述。     

肿瘤坏死因子相关细胞凋亡诱导配体表达载体的制备

目的构建一种携带肿瘤坏死因子相关细胞凋亡诱导配体（TRAIL）基因的重组腺相关病毒（rAAV）载体。方法首先构建携带可溶性肿瘤坏死因子相关细胞凋亡诱导配体（sTRAIL）基因的穿梭质粒腺相关病毒穿梭质粒-可溶性肿瘤坏死因子相关细胞凋亡诱导配体（pAAV-sTRAIL），将穿梭质粒转染入HEK293细胞（人胚肾细胞系）中，采用细胞内质粒DNA同源重组法构建重组腺相关病毒载体rAAV-sTRAIL。以噬斑分析法筛选单克隆rAAV-sTRAIL；PCR法鉴定阳性rAAV-sTRAIL；氯化铯密度梯度离心法纯化rAAV-sTRAIL；紫外分光光度仪测定rAAV-sTRAIL颗粒数及纯度，噬斑分析法测定rAAV-sTRAIL感染滴度；Western免疫印迹检测rAAV-sTRAIL在HEK293细胞中的表达情况。结果成功构建了rAAV-sTRAIL，制备的病毒纯度好、滴度高，且在HEK293转导细胞中能有效表达目的基因sTRAIL。结论构建的重组腺相关病毒载体rAAV-sTRAIL，为研究TRAIL抗肿瘤细胞效应及临床应用提供先进的载体系统。     

肿瘤坏死因子相关凋亡诱导配体及其诱导肿瘤细胞凋亡机制的研究进展

肿瘤坏死因子相关凋亡诱导配体(TRAIL)与死亡受体结合后，可启动凋亡信号的转导。它对肿瘤细胞的高效杀伤作用使其成为最具有潜力的肿瘤治疗药物，但在TRAIL的研究领域中仍然存在许多热点问题有待解决。本文综述了近年来TRAIL认几诱导肿瘤细胞凋亡的胞内机制、抗肿瘤活性及安全性问题的研究进展。     

Quantitative analysis of transferrin receptor 1 (TfR1) in individual breast cancer cells by means of labeled antibodies and elemental (ICP-MS) detection

化疗药物由于对肿瘤缺乏选择性而产生不同程度的不良反应,其临床应用受到了一定的限制。转铁蛋白受体(transferrin receptor,TfR)在多种肿瘤细胞和肿瘤相关血管过表达,而在正常细胞低表达,是肿瘤靶向递药系统的作用靶点之一。以对TfR具有特异性高亲和作用的配体修饰药物载体或偶联抗肿瘤药物,有望实现TfR过表达肿瘤的靶向治疗。本文综述了近年来TfR功能性配体在肿瘤靶向药物递送中的应用进展,以期为TfR靶向药物递送系统的研究提供思路。

     

TRAIL联用化疗药物抗妇科肿瘤的研究进展

肿瘤坏死因子相关凋亡诱导配体（TRAIL）因其选择性诱导肿瘤细胞凋亡的特点而受到关注。目前,TRAIL及其受体已被广泛运用于妇科肿瘤的治疗研究中,不同的妇科肿瘤细胞株对TRAIL诱导的凋亡敏感性不同,某些细胞株对TRAIL耐药。克服肿瘤细胞对TRAIL的耐药,同时保护正常细胞免受伤害,     

肿瘤坏死因子相关的凋亡诱导配体与肿瘤治疗

肿瘤坏死因子相关的凋亡诱导配体（TRAIL）或称凋亡素2配体（Apo2 ligand,Apo-2L）是1995年发现的TNF超家族的新成员。它的最大特点是可以选择性诱导肿瘤细胞和转化细胞发生凋亡,但对正常组织和细胞没有显著毒性效应。本文从TRAIL的结构、受体、凋亡机制及其在肿瘤治疗中的应用等方面对其进行了介绍。TRAIL很可能在肿瘤治疗方面发挥重要作用。     

应用组织芯片研究TRAIL OPG在浸润性乳腺癌中的表达及意义

<正>TRAIL即肿瘤坏死因子相关凋亡诱导配体(TNF-related apoptosis-inducing ligand),也称APO-2L(apoptosis-2 ligand)。它属于TNF超家族成员,被称为继FasL、肿瘤坏死因子(TNF)之后第3个死亡因子。TRAIL具有选择性诱导肿瘤细胞发生凋亡的作用,他的生物学效应是通过与其靶细胞膜上相应的     

TRAIL联合顺铂诱导三阴乳腺癌MDA-MB-231细胞过度性自噬的分子机制北大核心CSCD

流行病学报道,乳腺癌成为目前女性发病率和死亡率最高的癌症[1]。而铂类药物也是临床上最常用的周期非特异性抗肿瘤药物,在临床治疗实体肿瘤中显示了良好的疗效[2]。其中顺铂作为一线临床的传统用药,其靶点选择范围窄、疗效差、易耐药等问题,尚未得到解决。肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor-related apoptosis-inducing ligand,TRAIL)属于肿瘤坏死因子(tumor necrosis factor,TNF)超家族。     

肿瘤坏死因子相关凋亡诱导配体临床治疗应用前景

肿瘤坏死因子相关凋亡诱导配体(TRAIL)具有选择性细胞毒性,不仅诱导肿瘤细胞凋亡,还诱导肝和脑细胞凋亡,也诱导病毒感染的细胞凋亡,但对机体正常组织无毒性。TRAIL已成为全球新药研究的热点。本文从TRAIL的凋亡通路及其调控、肿瘤细胞对TRAIL抵抗的原因综述TRAIL在难治性疾病治疗中的应用。     

肿瘤细胞对TRAIL耐受机制以及克服耐受性的研究进展

TRAIL的全称是肿瘤坏死因子相关的凋亡诱导配体,也称为APO-2L,因为TRAIL与TNF和CD95/FasL具有同源性序列,因此确定TRAIL为TNF超家族成员之一,它属于Ⅱ型跨膜蛋白。到目前为止,研究重点关注于TRAIL诱导凋亡的作用机制和产生TRAIL耐受性的过程。化学疗法或放射疗法联合应用可使对TRAIL耐受的肿瘤恢复TRAIL敏感性。本综述关注TRAIL受体诱导的凋亡信号通路、肿瘤耐受TRAIL的机制以及可能克服耐受的方法。     

A novel tumor-homing TRAIL variant eradicates tumor xenografts of refractory colorectal cancer cells in combination with tumor cell-targeted photodynamic therapy

Multidrug resistance (MDR), which is common in colorectal cancer (CRC), induces high mortality in patients. Due to its robust and selective apoptosis induction in some CRC cells with MDR, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is attractive as a novel tool for CRC therapy. However, TRAIL is limited by its poor tumor-homing ability and inefficient apoptosis induction in CRC cells expressing low levels of death receptor (DR). Here, the tumor-homing RGR peptide (CRGRRST) was fused to TRAIL to produce RGR-TRAIL. Compared with TRAIL, RGR-TRAIL showed greater cell binding and cytotoxicity in CRC cells. In addition, RGR-TRAIL exerted significantly enhanced tumor uptake and growth suppression in mice bearing CRC tumor xenografts. Notably, RGR-TRAIL eradicated all tumor xenografts of DR-overexpressing COLO205 cells. However, TRAIL only showed mild tumor growth suppression under the same conditions, indicating that RGR fusion significantly increased the antitumor effect of TRAIL in DR-overexpressing CRC cells by improving tumor homing. Nevertheless, RGR fusion did not significantly enhance the antitumor effect of TRAIL in HT29 cells expressing low levels of DR. We found that DR expression in HT29 cells was enhanced by epidermal growth factor receptor (EGFR)-targeted photodynamic therapy (PDT). Moreover, both the in vitro and in vivo antitumor effects of RGR-TRAIL were significantly improved by combination with PDT. HT29 tumor xenografts (∼20%) were even eradicated by combination therapy. These results indicate that it is valuable to further evaluate the combination therapy of RGR-TRAIL and tumor-targeted PDT for clinical therapy of CRC with MDR.     

Butein sensitizes human leukemia cells to apoptosis induced by tumor necrosis factor-related apoptosis inducing ligand (TRAIL)

Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy is frequently encountered, requiring combined treatments with sensitizing agents. It is, therefore, important to find nontoxic drugs which can be used together with TRAIL. In this study, we investigated natural compounds that can overcome resistance to TRAIL, and found that butein, a polyphenol, exhibits significant synergism with TRAIL. Treatment with TRAIL in combination with subtoxic concentrations of butein sensitizes TRAIL-resistant human leukemia U937 cells to apoptosis. Butein increased caspase-3 activity and expression of death receptor DR5. The apoptotic cell death induced by combined treatment was significantly reduced by z-DEVD-fmk, a caspase-3 inhibitor, suggesting a critical role of caspase-3 in apoptosis. These results indicate that butein sensitizes TRAIL-resistant U937 cells to TRAIL-induced apoptosis in a caspase-3 dependent manner which might be correlated with upregulation of death receptor DR5. Our data suggests that combined treatment with butein and TRAIL may provide a safe and effective strategy for treating cancer.     

Targeting death receptors in cancer with Apo2L/TRAIL

Unlike conventional cancer therapeutics, death receptor ligands trigger tumor cell apoptosis independently of the p53 tumor suppressor gene, which frequently is inactivated in cancer. The death receptor ligand Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) offers promising therapeutic potential based on its ability to induce apoptosis in various cancer cell lines with little toxicity toward normal cells. Moreover, Apo2L/TRAIL displays single-agent activity and cooperates with chemotherapy or radiotherapy in a variety of tumor xenograft mouse models. Thus, Apo2L/TRAIL might be effective against tumors that have acquired resistance to conventional therapy, and could augment the efficacy of current treatment in a wide spectrum of cancers.     

Harnessing tumor necrosis factor receptors to enhance antitumor activities of drugs

Cancer is the second-leading cause of death in the U.S. behind heart disease and over stroke. The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The inhibition of cell death pathways is one of these tumor characteristics which also include sustained proliferative signaling, evading growth suppressor signaling, replicative immortality, angiogenesis, and promotion of invasion and metastasis. Cell death is mediated through death receptor (DR) stimulation initiated by specific ligands that transmit signaling to the cell death machinery or through the participation of mitochondria. Cell death involving DR is mediated by the superfamily of tumor necrosis factor receptor (TNF-R) which includes TNF-R type I, CD95, DR3, TNF-related apoptosis-inducing ligand (TRAIL) receptor-1 (TRAIL-R1) and -2 (TRAIL-R2), DR6, ectodysplasin A (EDA) receptor (EDAR), and the nerve growth factor (NGF) receptor (NGFR). The expression of these receptors in healthy and tumor cells induces treatment side effects that limit the systemic administration of cell death-inducing therapies. The present review is focused on the different therapeutic strategies such as targeted antibodies or small molecules addressed to selective stimulated DR-mediated apoptosis or reduce cell proliferation in cancer cells.     

Camptothecin sensitizes human hepatoma Hep3B cells to TRAIL-mediated apoptosis via ROS-dependent death receptor 5 upregulation with the involvement of MAPKs

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various types of malignant cancer cells, but several cancers have acquired potent resistance to TRAIL-induced cell death by unknown mechanisms. Camptothecin (CPT) is a quinolone alkaloid that induces cytotoxicity in a variety of cancer cell lines. However, it is not known whether CPT triggers TRAIL-induced cell death. In this study, we found that combined treatment with subtoxic doses of CPT and TRAIL (CPT-TRAIL) potentially enhanced apoptosis in a caspase-dependent manner. CPT-TRAIL effectively induced the expression of death receptor (DR) 5, which is a specific receptor of TRAIL, and treatment with a chimeric blocking antibody for DR5 reduced CPT-TRAIL-induced cell death, indicating that CPT functionally triggers DR5-mediated cell death in response to TRAIL. CPT-induced generation of reactive oxygen species (ROS) also preceded the upregulation of DR5 in response to TRAIL. The involvement of ROS in DR5 upregulation confirmed that pretreatment with antioxidants, including N-acetyl-L-cysteine and glutathione, significantly inhibits CPT-TRAIL-induced cell death by suppressing DR5 expression. The specific inhibitors of ERK and p38 also decreased CPT-TRAIL-induced cell death by blocking DR5 expression. In conclusion, our results suggest that CPT sensitizes cancer cells to TRAIL-mediated apoptosis via ROS and ERK/p38-dependent DR5 upregulation.     

Targeting TRAIL towards the clinic

Tumor necrosis factor-related apoptosis-inducing ligand or Apo2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis upon binding to its death domain-containing transmembrane receptors. The preferential toxicity of TRAIL to cancer cells and the sparing of normal cells make it an ideal cancer therapeutic agent. TRAIL induces apoptosis via the extrinsic death receptor apoptotic pathway and activates the JNK, ERK, Akt and NF-κB signaling cascades. However, not all cancer cells are sensitive to TRAIL therapy. This may limit its efficacy in the clinic, although ways have already been identified to overcome resistance by combining TRAIL with chemotherapeutic and other biological agents. This review focuses on TRAIL receptor-targeting as anticancer therapy, the apoptotic signaling pathways induced by TRAIL receptors, the prognostic implications of TRAIL receptor expression and modulation by combination therapies. The mechanisms of TRAIL resistance and strategies to overcome drug resistance will also be addressed. Finally, the progress of TRAIL and DR4/DR5-specific agonistic antibodies in clinical trials and the development of new receptor-selective TRAIL variants are discussed including future directions for apoptosis inducing therapy.     

肿瘤坏死因子相关凋亡诱导配体与肿瘤免疫

TRAIL是肿瘤坏死因子超家族成员,广泛表达于多种组织细胞。TRAIL与其受体结合后,可启动信号转导,选择性地诱导肿瘤细胞凋亡,而对正常细胞毒性小或无损伤。一些药物和细胞因子可协同TRAIL诱导肿瘤细胞凋亡。但肿瘤细胞也可通过表达TRAIL,产生免疫逃逸或免疫赦免,且TRAIL的作用还受到NFκB或靶细胞表达TRAIL受体类型和数量的影响。     

Antitumor activity of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand

AIM: To investigate the antitumor activity and safety of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand (rmh TRAIL). METHODS: Antitumor activity of rmh TRAIL was evaluated by using several tumor cell lines by MTT assay in vitro, and by using a mouse xenograft model in vivo. rmh TRAIL-induced apoptosis in tumor cells was detected by cell death enzyme-linked immunosorbent assay (ELISA), TdT-mediated dUTP nick-end labeling (TUNEL) assay and flow cytometry. The safety of rmh TRAIL was also evaluated in several normal human cell lines. RESULTS: At the concentration of 0.32-1 000 ng/mL, rmh TRAIL remarkably inhibited the proliferation of 5 tumor cell lines from lung, colon, and breast cancer compared with wild type (wt TRAIL) in vitro, whereas at the concentration of 1 ng/mL-10 microg/mL, rmh TRAIL showed no or mild cytotoxicity in the normal cell lines. rmh TRAIL (3, 15 mg/kg, ip, once daily for 10 d) exerted a significant inhibition on the growth of xenograft tumor NCI-H460 in nude mice compared with the saline group (P<0.01), and was more potent than wt TRAIL, a positive control. The apoptosis of NCI-H460 cells was markedly induced in a concentration-dependent and time-dependent manner after rmh TRAIL treatment. The percentage of apoptotic cells induced by rmh TRAIL in NCI-H460 cells was significantly higher than that by wt TRAIL. CONCLUSION: rmh TRAIL provided potent antitumor activity in vivo and in vitro, whereas most normal human cells were resistant to rmh TRAIL. The results suggested that rmh TRAIL might be a useful anticancer agent in future.     

Down-Regulation of Survivin by Nemadipine-A Sensitizes Cancer Cells to TRAIL-Induced Apoptosis

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines. TRAIL selectively induces apoptotic cell death in various tumors and cancer cells, but it has little or no toxicity in normal cells. Agonism of TRAIL receptors has been considered to be a valuable cancer-therapeutic strategy. However, more than 85% of primary tumors are resistant to TRAIL, emphasizing the importance of investigating how to overcome TRAIL resistance. In this report, we have found that nemadipine-A, a cell-permeable L-type calcium channel inhibitor, sensitizes TRAIL-resistant cancer cells to this ligand. Combination treatments using TRAIL with nemadipine-A synergistically induced both the caspase cascade and apoptotic cell death, which were blocked by a pan caspase inhibitor (zVAD) but not by autophagy or a necrosis inhibitor. We further found that nemadipine-A, either alone or in combination with TRAIL, notably reduced the expression of survivin, an inhibitor of the apoptosis protein (IAP) family of proteins. Depletion of survivin by small RNA interference (siRNA) resulted in increased cell death and caspase activation by TRAIL treatment. These results suggest that nemadipine-A potentiates TRAIL-induced apoptosis by down-regulation of survivin expression in TRAIL resistant cells. Thus, combination of TRAIL with nemadipine-A may serve a new therapeutic scheme for the treatment of TRAIL resistant cancer cells, suggesting that a detailed study of this combination would be useful.