Holoch PA, Griffith TS.. TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies. Eur J Pharmacol 625: 63-72

Department of Urology, University of Iowa, 375 Newton Road, Iowa City, IA 52242, USA.
European journal of pharmacology (Impact Factor: 2.53). 10/2009; 625(1-3):63-72. DOI: 10.1016/j.ejphar.2009.06.066
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ABSTRACT Since its discovery in 1995, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor super family, has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. Consequently, activation of the apoptotic signaling pathway from the death-inducing TRAIL receptors provides an attractive, biologically-targeted approach to cancer therapy. A great deal of research has focused on deciphering the TRAIL receptor signaling cascade and intracellular regulation of this pathway, as many human tumor cells possess mechanisms of resistance to TRAIL-induced apoptosis. This review focuses on the current state of knowledge regarding TRAIL signaling and resistance, the preclinical development of therapies targeted at TRAIL receptors and modulators of the pathway, and the results of clinical trials for cancer treatment that have emerged from this base of knowledge. TRAIL-based approaches to cancer therapy vary from systemic administration of recombinant, soluble TRAIL protein with or without the combination of traditional chemotherapy, radiation or novel anti-cancer agents to agonistic monoclonal antibodies directed against functional TRAIL receptors to TRAIL gene transfer therapy. A better understanding of TRAIL resistance mechanisms may allow for the development of more effective therapies that exploit this cell-mediated pathway to apoptosis.

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Available from: Thomas S Griffith, Sep 28, 2015
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    • "We observed that induction of miR-139-5p mediated apoptosis occurs by the modulation of extrinsic apoptosis pathway. Apoptosis induced by extrinsic pathways has been considered to be an important antitumor mechanism [30-32]. After transfection with miR-139-5p, the protein expression of the downstream active apoptosis executors caspase-8, caspase-7, caspase-3 was upregulated and enhanced level of cleaved PARP indicated caspase 3 was functionally active (Figure 3D). "
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    ABSTRACT: Background miR-139-5p was identified to be significantly down-regulated in colon tumor tissues by miRNA array. We aimed to clarify its biological function, molecular mechanisms and direct target gene in colorectal cancer (CRC). Methods The biological function of miR-139-5p was examined by cell growth, cell cycle and apoptosis analysis in vitro and in vivo. miR-139-5p target gene and signaling pathway was identified by luciferase activity assay and western blot. Results miR-139-5p was significantly down-regulated in primary tumor tissues (P < 0.0001). Ectopic expression of miR-139-5p in colon cancer cell lines significantly suppressed cell growth as evidenced by cell viability assay (P < 0.001) and colony formation assay (P < 0.01) and in xenograft tumor growth in nude mice (P < 0.01). miR-139-5p induced apoptosis (P < 0.01), concomitantly with up-regulation of key apoptosis genes including cleaved caspase-8, caspase-3, caspase-7 and PARP. miR-139-5p also caused cell cycle arrest in G0/G1 phase (P < 0.01), with upregulation of key G0/G1 phase regulators p21Cip1/Waf1 and p27Kip1. Moreover, miR-139-5p inhibited cellular migration (P < 0.001) and invasiveness (P < 0.001) through the inhibition of matrix metalloproteinases (MMP)7 and MMP9. Oncogene NOTCH1 was revealed to be a putative target of miR-139-5p, which was inversely correlated with miR-139-5p expression (r = -0.3862, P = 0.0002). Conclusions miR-139-5p plays a pivotal role in colon cancer through inhibiting cell proliferation, metastasis, and promoting apoptosis and cell cycle arrest by targeting oncogenic NOTCH1.
    Molecular Cancer 05/2014; 13(1):124. DOI:10.1186/1476-4598-13-124 · 4.26 Impact Factor
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    • "HVJ-E-mediated cell growth inhibition of PC3 was suppressed by the knockdown of RIG-I and MAVS, indicating that the RIG-I/MAVS signaling pathway is important for this process. Moreover, HVJ-E treatment induced the expression of TRAIL and Noxa (known as apoptosis inducers [98, 99]) in PC3 and DU145 cells, but not in PNT2 cells, via RIG-I/MAVS signaling. The fact that the knockdown of TRAIL and Noxa suppressed the HVJ-E sensitivity of PC3 and DU145, respectively, indicates that these apoptosis inducers are responsible for HVJ-E-induced cancer cell apoptosis. "
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    ABSTRACT: A virosome is an artificial envelope that includes viral surface proteins and lacks the ability to produce progeny virus. Virosomes are able to introduce an encapsulated macromolecule into the cytoplasm of cells using their viral envelope fusion ability. Moreover, virus-derived factors have an adjuvant effect for immune stimulation. Therefore, many virosomes have been utilized as drug delivery vectors and adjuvants for cancer therapy. This paper introduces the application of virosomes for cancer treatment. In Particular, we focus on virosomes derived from the influenza and Sendai viruses which have been widely used for cancer therapy. Influenza virosomes have been mainly applied as drug delivery vectors and adjuvants. By contrast, the Sendai virosomes have been mainly applied as anticancer immune activators and apoptosis inducers.
    12/2013; 2013(5038):764706. DOI:10.1155/2013/764706
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    • "Activation of caspase-8 further leads to two different apoptotic pathways depending on the cell type. TRAIL induces apoptosis in a mitochondrial-independent manner (extrinsic), activating downstream effecter caspases such as caspase-3, whereas a mitochondrial-dependent pathway (intrinsic) proceeds via the activation of caspase-9, which then induces the execution phase of apoptosis [25]. In this study, the expression of procaspase-3, procaspase-8, and procaspase-9 was decreased in 5-Fu, TRAIL, and combined groups, especially in TRAIL and combined groups (P < 0.01) compared with control group. "
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    ABSTRACT: The TNF-related apoptosis-inducing ligand (TRAIL) is a TNF family member which has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. However, many cancer cells remain resistant to TRAIL. In this study, we had investigated the synergistic effects of low dose fluorouracil (5-Fu) and TRAIL on TRAIL-resistant human gastric adenocarcinoma AGS cells and explored the potential mechanisms. Cell viability was analyzed by sulforhodamine B (SRB) assay and the synergistic effects were evaluated by Jin's formula and confirmed by both morphological changes under inverted microscope and flow cytometry. The expression of TRAIL-R1 (death receptor 4, DR4), TRAIL-R2 (DR5), TRAIL-R3 (decoy receptor, DcR1), TRAIL-R4 (DcR2), procaspase-3, procaspase-8, and procaspase-9 was detected by western blotting. Our results showed that there were significant synergistic effects of low dose 5-Fu and TRAIL on TRAIL-resistant AGS cells, and this effect was supposed to be mediated by decreasing DcR2 expression and increasing DR5 expression. The extrinsic and intrinsic apoptosis pathways were both activated. The data suggest that combined treatment of low dose 5-Fu and TRAIL can be an effective therapeutic approach for gastric adenocarcinoma.
    11/2013; 2013(2):293874. DOI:10.1155/2013/293874
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