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A novel caspase 8 selective small molecule potentiates TRAIL-induced cell death.

Recombinant soluble TRAIL and agonistic antibodies against TRAIL receptors (DR4 and DR5) are currently being created for clinical cancer therapy, due to their selective killing of cancer cells and high safety characteristics. However, resistance to TRAIL and other targeted therapies is an important... Full description

Journal Title: Scientific reports May 11, 2015, Vol.5, p.9893
Main Author: Bucur, Octavian
Other Authors: Gaidos, Gabriel , Yatawara, Achani , Pennarun, Bodvael , Rupasinghe, Chamila , Roux, Jérémie , Andrei, Stefan , Guo, Bingqian , Panaitiu, Alexandra , Pellegrini, Maria , Mierke, Dale F , Khosravi-Far, Roya
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 2045-2322 ; DOI: 10.1038/srep09893
Link: http://search.proquest.com/docview/1680748962/?pq-origsite=primo
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recordid: proquest1680748962
title: A novel caspase 8 selective small molecule potentiates TRAIL-induced cell death.
format: Article
creator:
  • Bucur, Octavian
  • Gaidos, Gabriel
  • Yatawara, Achani
  • Pennarun, Bodvael
  • Rupasinghe, Chamila
  • Roux, Jérémie
  • Andrei, Stefan
  • Guo, Bingqian
  • Panaitiu, Alexandra
  • Pellegrini, Maria
  • Mierke, Dale F
  • Khosravi-Far, Roya
subjects:
  • Apoptosis–Drug Effects
  • Caspase 8–Genetics
  • Enzyme Activation–Chemistry
  • Enzyme Activators–Genetics
  • Hela Cells–Metabolism
  • Humans–Drug Effects
  • Jurkat Cells–Genetics
  • K562 Cells–Chemistry
  • Neoplasm Proteins–Pharmacology
  • Neoplasms–Agonists
  • Receptors, Tnf-Related Apoptosis-Inducing Ligand–Genetics
  • Tnf-Related Apoptosis-Inducing Ligand–Metabolism
  • Tnf-Related Apoptosis-Inducing Ligand–Drug Therapy
  • Tnf-Related Apoptosis-Inducing Ligand–Genetics
  • Tnf-Related Apoptosis-Inducing Ligand–Metabolism
  • Tnf-Related Apoptosis-Inducing Ligand–Pathology
  • Tnf-Related Apoptosis-Inducing Ligand–Agonists
  • Tnf-Related Apoptosis-Inducing Ligand–Genetics
  • Tnf-Related Apoptosis-Inducing Ligand–Metabolism
  • Tnf-Related Apoptosis-Inducing Ligand–Genetics
  • Tnf-Related Apoptosis-Inducing Ligand–Metabolism
  • Enzyme Activators
  • Neoplasm Proteins
  • Receptors, Tnf-Related Apoptosis-Inducing Ligand
  • Tnf-Related Apoptosis-Inducing Ligand
  • Tnfrsf10a Protein, Human
  • Tnfsf10 Protein, Human
  • Casp8 Protein, Human
  • Caspase 8
ispartof: Scientific reports, May 11, 2015, Vol.5, p.9893
description: Recombinant soluble TRAIL and agonistic antibodies against TRAIL receptors (DR4 and DR5) are currently being created for clinical cancer therapy, due to their selective killing of cancer cells and high safety characteristics. However, resistance to TRAIL and other targeted therapies is an important issue facing current cancer research field. An attractive strategy to sensitize resistant malignancies to TRAIL-induced cell death is the design of small molecules that target and promote caspase 8 activation. For the first time, we describe the discovery and characterization of a small molecule that directly binds caspase 8 and enhances its activation when combined with TRAIL, but not alone. The molecule was identified through an in silico chemical screen for compounds with affinity for the caspase 8 homodimer's interface. The compound was experimentally validated to directly bind caspase 8, and to promote caspase 8 activation and cell death in single living cells or population of cells, upon TRAIL stimulation. Our approach is a proof-of-concept strategy leading to the discovery of a novel small molecule that not only stimulates TRAIL-induced apoptosis in cancer cells, but may also provide insights into the structure-function relationship of caspase 8 homodimers as putative targets in cancer.
language: eng
source:
identifier: E-ISSN: 2045-2322 ; DOI: 10.1038/srep09893
fulltext: fulltext
issn:
  • 20452322
  • 2045-2322
url: Link


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titleA novel caspase 8 selective small molecule potentiates TRAIL-induced cell death.
creatorBucur, Octavian ; Gaidos, Gabriel ; Yatawara, Achani ; Pennarun, Bodvael ; Rupasinghe, Chamila ; Roux, Jérémie ; Andrei, Stefan ; Guo, Bingqian ; Panaitiu, Alexandra ; Pellegrini, Maria ; Mierke, Dale F ; Khosravi-Far, Roya
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ispartofScientific reports, May 11, 2015, Vol.5, p.9893
identifierE-ISSN: 2045-2322 ; DOI: 10.1038/srep09893
subjectApoptosis–Drug Effects ; Caspase 8–Genetics ; Enzyme Activation–Chemistry ; Enzyme Activators–Genetics ; Hela Cells–Metabolism ; Humans–Drug Effects ; Jurkat Cells–Genetics ; K562 Cells–Chemistry ; Neoplasm Proteins–Pharmacology ; Neoplasms–Agonists ; Receptors, Tnf-Related Apoptosis-Inducing Ligand–Genetics ; Tnf-Related Apoptosis-Inducing Ligand–Metabolism ; Tnf-Related Apoptosis-Inducing Ligand–Drug Therapy ; Tnf-Related Apoptosis-Inducing Ligand–Genetics ; Tnf-Related Apoptosis-Inducing Ligand–Metabolism ; Tnf-Related Apoptosis-Inducing Ligand–Pathology ; Tnf-Related Apoptosis-Inducing Ligand–Agonists ; Tnf-Related Apoptosis-Inducing Ligand–Genetics ; Tnf-Related Apoptosis-Inducing Ligand–Metabolism ; Tnf-Related Apoptosis-Inducing Ligand–Genetics ; Tnf-Related Apoptosis-Inducing Ligand–Metabolism ; Enzyme Activators ; Neoplasm Proteins ; Receptors, Tnf-Related Apoptosis-Inducing Ligand ; Tnf-Related Apoptosis-Inducing Ligand ; Tnfrsf10a Protein, Human ; Tnfsf10 Protein, Human ; Casp8 Protein, Human ; Caspase 8
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descriptionRecombinant soluble TRAIL and agonistic antibodies against TRAIL receptors (DR4 and DR5) are currently being created for clinical cancer therapy, due to their selective killing of cancer cells and high safety characteristics. However, resistance to TRAIL and other targeted therapies is an important issue facing current cancer research field. An attractive strategy to sensitize resistant malignancies to TRAIL-induced cell death is the design of small molecules that target and promote caspase 8 activation. For the first time, we describe the discovery and characterization of a small molecule that directly binds caspase 8 and enhances its activation when combined with TRAIL, but not alone. The molecule was identified through an in silico chemical screen for compounds with affinity for the caspase 8 homodimer's interface. The compound was experimentally validated to directly bind caspase 8, and to promote caspase 8 activation and cell death in single living cells or population of cells, upon TRAIL stimulation. Our approach is a proof-of-concept strategy leading to the discovery of a novel small molecule that not only stimulates TRAIL-induced apoptosis in cancer cells, but may also provide insights into the structure-function relationship of caspase 8 homodimers as putative targets in cancer.
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