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以天然产物靶向肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体作为癌症治疗的一种潜在治疗方法。

Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy.

作者信息

Dai Xiaoyun, Zhang Jingwen, Arfuso Frank, Chinnathambi Arunachalam, Zayed M E, Alharbi Sulaiman Ali, Kumar Alan Prem, Ahn Kwang Seok, Sethi Gautam

机构信息

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.

School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University, Western Australia 6009, Australia.

出版信息

Exp Biol Med (Maywood). 2015 Jun;240(6):760-73. doi: 10.1177/1535370215579167. Epub 2015 Apr 7.

DOI:10.1177/1535370215579167
PMID:25854879
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4935211/
Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to selectively induce apoptotic cell death in various tumor cells by engaging its death-inducing receptors (TRAIL-R1 and TRAIL-R2). This property has led to the development of a number of TRAIL-receptor agonists such as the soluble recombinant TRAIL and agonistic antibodies, which have shown promising anticancer activity in preclinical studies. However, besides activating caspase-dependent apoptosis in several cancer cells, TRAIL may also activate nonapoptotic signal transduction pathways such as nuclear factor-kappa B, mitogen-activated protein kinases, AKT, and signal transducers and activators of transcription 3, which may contribute to TRAIL resistance that is being now frequently encountered in various cancers. TRAIL resistance can be overcome by the application of efficient TRAIL-sensitizing pharmacological agents. Natural compounds have shown a great potential in sensitizing cells to TRAIL treatment through suppression of distinct survival pathways. In this review, we have summarized both apoptotic and nonapoptotic pathways activated by TRAIL, as well as recent advances in developing TRAIL-receptor agonists for cancer therapy. We also briefly discuss combination therapies that have shown great potential in overcoming TRAIL resistance in various tumors.

摘要

肿瘤坏死因子相关凋亡诱导配体（TRAIL）已被证明可通过与死亡诱导受体（TRAIL-R1和TRAIL-R2）结合，在多种肿瘤细胞中选择性地诱导凋亡性细胞死亡。这一特性促使了多种TRAIL受体激动剂的研发，如可溶性重组TRAIL和激动性抗体，它们在临床前研究中已显示出有前景的抗癌活性。然而，除了在几种癌细胞中激活半胱天冬酶依赖性凋亡外，TRAIL还可能激活非凋亡信号转导途径，如核因子-κB、丝裂原活化蛋白激酶、AKT以及信号转导和转录激活因子3，这些可能导致目前在各种癌症中经常遇到的TRAIL耐药性。通过应用有效的TRAIL增敏药理学药物可以克服TRAIL耐药性。天然化合物已显示出通过抑制不同的生存途径使细胞对TRAIL治疗敏感的巨大潜力。在这篇综述中，我们总结了TRAIL激活的凋亡和非凋亡途径，以及开发用于癌症治疗的TRAIL受体激动剂的最新进展。我们还简要讨论了在克服各种肿瘤中的TRAIL耐药性方面显示出巨大潜力的联合疗法。

相似文献

[1]
Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy.

Exp Biol Med (Maywood). 2015-6

[2]
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[3]
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[4]
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Biochem Pharmacol. 2012-1-2

[5]
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Expert Opin Ther Targets. 2010-10

[6]
The anti-CD20 mAb LFB-R603 interrupts the dysregulated NF-κB/Snail/RKIP/PTEN resistance loop in B-NHL cells: role in sensitization to TRAIL apoptosis.

Int J Oncol. 2011-3-23

[7]
Kinome profiling of non-canonical TRAIL signaling reveals RIP1-Src-STAT3-dependent invasion in resistant non-small cell lung cancer cells.

J Cell Sci. 2012-7-13

[8]
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[9]
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Int J Oncol. 2008-8

[10]
TRAIL-mediated apoptosis requires NF-kappaB inhibition and the mitochondrial permeability transition in human hepatoma cells.

Hepatology. 2002-12

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[2]
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Int J Oncol. 2025-6

[3]
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Exp Cell Res. 2025-4-1

[4]
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Adv Sci (Weinh). 2025-4

[5]
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Cells. 2024-11-6

[6]
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[7]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
The pleiotropic profile of the indirubin derivative 6BIO overcomes TRAIL resistance in cancer.

Biochem Pharmacol. 2014-9-15

[2]
Getting TRAIL back on track for cancer therapy.

Cell Death Differ. 2014-9

[3]
Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells.

Int J Oncol. 2014-3-10

[4]
Phase II trial of mapatumumab, a fully human agonist monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer.

Clin Lung Cancer. 2014-5

[5]
Luteolin sensitizes human 786-O renal cell carcinoma cells to TRAIL-induced apoptosis.

Life Sci. 2014-2-14

[6]
Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer.

Cancer Med. 2013-10-25

[7]
A randomized, double-blind, placebo-controlled phase 2 study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naïve metastatic/unresectable non-small cell lung cancer.

Lung Cancer. 2013-10-1

[8]
TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first-line treatment of metastatic colorectal cancer: A randomized phase 1b/2 trial.

Cancer. 2013-10-1

[9]
Azadirone, a limonoid tetranortriterpene, induces death receptors and sensitizes human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through a p53 protein-independent mechanism: evidence for the role of the ROS-ERK-CHOP-death receptor pathway.

J Biol Chem. 2013-9-27

[10]
A phase 1B study of dulanermin in combination with modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer.

Clin Colorectal Cancer. 2013-9-27

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