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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 总被引:2,自引:0,他引:2
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。 相似文献
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肿瘤坏死因子相关凋亡诱导配体(TRAIL)是近年来发现的凋亡分子,能选择性诱导转化细胞、肿瘤细胞和病毒感染细胞发生凋亡,而对大多数正常细胞几乎没有毒性。但如果TRAIL在肿瘤中介导的凋亡信号传递受阻或者出现其他信号传导通路的激活,就可引起肿瘤对TRAIL的耐受。如果TRAIL蛋白与化疗药物或其他方法联合应用,就可以上调DR4、DR5、caspase3、caspase8或Bax等促凋亡因子的表达,或下调Bcl-XL、cFLIP等凋亡抑制因子的表达,从而克服肿瘤细胞对TRAIL的耐受或提高对TRAIL的敏感性。本文主要概述肿瘤细胞对TRAIL的耐受机制及克服耐受、增强肿瘤细胞凋亡敏感性的实验研究进展。 相似文献
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肿瘤坏死相关凋亡诱导配体(TNF-related apoptosis-inducing ligand,TRAIL),也称为凋亡素2配体(Apoptosisin 2 Ligand,Apo2L),是肿瘤坏死因子超家族成员,能够激发肿瘤细胞选择性地发生凋亡,并对正常组织细胞几乎无毒性。TRAIL通过细胞表达受体,即死亡受体4和5(Death Receptor 4,DR4 and Death Receptor5)发挥作用,而大多数肿瘤细胞表面表达这2种受体。为了深入研究TRAIL在肿瘤治疗中的价值,我们采用RT-PCR方法克隆了TRAIL基因,并对其细胞外可溶性区域(114-281氨基酸残基)在大肠杆菌中进行了表达。重组的TRAIL可溶性蛋白占细菌总蛋白的45%以上,初步分析具有TRAIL的生物学活性。 相似文献
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TRAIL及其受体的研究进展 总被引:2,自引:0,他引:2
TRAIL(TNFrelatedapoptosis inducingligand)及其受体属于肿瘤坏死因子超基因家族成员 ,在细胞的凋亡调控中起着重要的作用。TRAIL能诱导多种肿瘤细胞的凋亡 ,而正常组织细胞对其不敏感 ,提示TRAIL可能成为一种新的抗肿瘤药物。 相似文献
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肿瘤细胞对TRAIL耐受机制以及克服耐受性的研究进展 总被引:1,自引:0,他引:1
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。 相似文献
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肿瘤坏死因子相关凋亡诱导配体(Tumor necrosis factor-related apoptosis-inducing ligand,TRAIL)是肿瘤坏死因子家族的成员之一,可与肿瘤细胞膜表面过度表达的死亡受体4或5结合,特异性诱导肿瘤细胞凋亡,且对正常细胞无明显影响,因此被认为是临床最有发展前景的蛋白药物之一。然而,由于肿瘤坏死因子相关凋亡诱导配体存在体内稳定性差和生物利用度低等缺点,限制了其在临床中的应用。运用药物载体对肿瘤坏死因子相关凋亡诱导配体进行递送,成为目前解决此弊端的有效策略。本综述简要介绍了近年来药物载体在肿瘤坏死因子相关凋亡诱导配体递送方面的研究进展。 相似文献
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Induction of apoptosis in tumor cells is a major goal for chemotherapy and radiation treatment strategies. However, disordered gene expression often leads to apoptosis resistance rendering tumor cells insensitive to various conventional treatments. TNF-related apoptosis-inducing ligand (TRAIL) is a recently identified cytokine of the TNF superfamily that induces apoptosis in tumor cells upon binding to different receptors. Remarkably, the majority of tumor cell lines are sensitive to TRAIL-induced apoptosis, while most nontransformed cell types are TRAIL-resistant. Furthermore, a combination treatment of TRAIL with ionizing irradiation or chemotherapeutic agents induces apoptosis in a highly synergistic manner, particularly in those cells that are otherwise resistant to a sole treatment. In contrast to other TNF members, TRAIL apparently does not exert overt systemic toxicity in murine and primate models, although unexpected concerns about a potential hepatotoxicity of TRAIL have been recently raised. While the molecular mechanisms of TRAIL sensitivity and resistance are poorly understood, TRAIL seems to be a promising biological agent for combination therapy with chemotherapeutic drugs or irradiation. 相似文献
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Antitumor activity of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand 总被引:1,自引:1,他引:0
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. 相似文献
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目的探讨凋亡抑制蛋白(inhibitor of apoptosis pro-teins,IAP)在调节胃癌细胞对肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor-related apoptosis-inducing ligand,TRAIL)敏感性方面的作用。方法 PI染色流式细胞术检测细胞凋亡;Western blot检测caspase-3、PARP、XIAP、Survivin、cIAP1和cIAP2的表达。结果 TRAIL能诱导胃癌细胞凋亡,BGC-823细胞较SGC-7901细胞对TRAIL更敏感。caspase-3的活化及PARP的裂解在TRAIL作用早期即出现,且BGC-823细胞较SGC-7901细胞发生得更快。4种IAP蛋白在两株胃癌细胞中都组成性地高表达,Survivin和cIAP1在TRAIL处理前后无变化。而XIAP在BGC-823细胞中明显下降,在SGC-7901细胞中无改变。cIAP2在TRAIL作用后两株细胞中均有所降低。结论 TRAIL诱导胃癌细胞凋亡可能在活化的caspase-3水平受调控,XIAP能保护胃癌细胞免于凋亡。 相似文献
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Yamamoto K Makino M Watanapokasin R Tashiro E Imoto M 《The Journal of antibiotics》2012,65(6):295-300
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered as a possible therapeutic agent for cancer treatment. This is because of its selective cytotoxicity against various cancer cells without a detrimental effect on normal cells. However, recent studies have reported that the potential application of TRAIL in cancer therapy is limited, as many cancer cells have been found to be resistant to TRAIL. Therefore, small molecule compounds that potentiate the cytotoxicity of TRAIL would be strategic candidates for therapeutic applications in combination with TRAIL. Here we found that a combined treatment of inostamycin and TRAIL synergistically induced caspase-dependent apoptosis in HCT116 cells. Inostamycin upregulated DR5, and a knockdown of DR5 suppressed the apoptosis that was synergistically induced by co-treatment with inostamycin and TRAIL. Moreover, inostamycin increased the expression of DR5 on the cell surface. Therefore, inostamycin-increased cell surface expression of DR5 may have contributed to the enhancement of TRAIL-induced apoptosis. Our study suggests that combined treatment with inostamycin and TRAIL may offer a strategy to overcome TRAIL resistance in tumor cells. 相似文献
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Angelicin potentiates TRAIL‐induced apoptosis in renal carcinoma Caki cells through activation of caspase 3 and down‐regulation of c‐FLIP expression
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Kyoung‐Jin Min Hee Jung Um Seung Un Seo Seon Min Woo Shin Kim Jong‐Wook Park Hyun‐Shik Lee Sang Hyun Kim Yung Hyun Choi Tae‐Jin Lee Taeg Kyu Kwon 《Drug development research》2018,79(1):3-10
Preclinical Research & Development |
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Targeting death receptors in cancer with Apo2L/TRAIL 总被引:22,自引:0,他引:22
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. 相似文献
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Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) induces apoptosis in various cancer cells. Diarylheptanoids
such as hirsutenone and oregonin have been shown to have anti-inflammatory and anti-tumor effects. However, it is still unknown
by which mechanism diarylheptanoids induce cell death. In addition, the effect of hirsutenone on TRAIL-induced apoptosis in
the human epithelial ovarian carcinoma cell lines is unknown. To assess the apoptosis promoting effect of hirsutenone, we
investigated the effect of hirsutenone on the apoptotic effect of TRAIL using the human epithelial carcinoma cell lines OVCAR-3
and SK-OV-3. TRAIL induced nuclear damage, decrease in Bid, Bcl-2 and Bcl-xL protein levels, increase in Bax levels, loss
of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (8, 9 and 3) and increase in tumor suppressor p53 levels. Hirsutenone enhanced the TRAIL-induced
apoptosis-related protein activation, nuclear damage and cell death. The results suggest that hirsutenone may enhance the
apoptotic effect of TRAIL on ovarian carcinoma cell lines by increasing the activation of the caspase-8- and Bid-dependent
pathways and the mitochondria-mediated apoptotic pathway, leading to caspase activation. Hirsutenone may confer a benefit
in the TRAIL treatment of epithelial ovarian adenocarcinoma. 相似文献
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The death receptors CD95, TRAILR1 and TRAILR2 induce cell death in many types of tumor cells. Activation of these receptors has received considerable interest due to its potential use in cancer therapy. In particular the observation that most primary cells are not or only barely TRAIL-sensitive resulted in the development of targeted therapy concepts that base on activation of the TRAIL death receptors by recombinant TRAIL or agonistic antibodies. Indeed, a variety of preclinical studies and several phase I and II clinical trials show that activation of TRAIL death receptors effectively induces apoptosis in cancer cells in vivo without therapy-limiting toxicity on normal cells. Primary tumor cells are often sparsely sensitive for TRAIL death receptor-mediated apoptosis or acquire resistance during therapy. Sensitization/resensitization of tumor cells by chemotherapeutic drugs or radiation can therefore be necessary for TRAIL-based therapies, but this involves the danger of triggering side effects related to the breakage of apoptosis resistance of non-transformed cells. Thus, there is a foreseeable need to develop optimized combination therapies or to locally restrict TRAIL receptor activation to fully exploit the antitumoral potential of TRAIL death receptors in the clinic. Although the high sensitivity of hepatocytes for CD95-mediated apoptosis prohibits therapies resulting in systemic activation of CD95, several studies have shown that this limitation can be overcome by ex vivo treatment regimes or by CD95 activating agonists with cell type-specific activity. This patent review is focused on the death receptor agonists currently under consideration in clinical trials, but also addresses the hurdles that have to be cleared to broaden and to improve the applicability of the currently used clinical concepts related to death receptor activation. 相似文献
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Seong Ho Park So Jung Park Joo-Oh Kim Ji Hyun Shin Eun Sung Kim Yoon Kyung Jo Jae-Sung Kim So Jung Park Dong-Hoon Jin Jung Jin Hwang Seung Jin Lee Seong-Yun Jeong Chaeyoung Lee InKi Kim Dong-Hyung Cho 《Biomolecules & therapeutics.》2013,21(1):29-34
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. 相似文献