Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-12

AUTHORS

Joshua E Allen, Gabriel Krigsfeld, Luv Patel, Patrick A Mayes, David T Dicker, Gen Sheng Wu, Wafik S El-Deiry

ABSTRACT

BACKGROUND: We previously reported the identification of ONC201/TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in advanced cancers based on its promising safety and antitumor efficacy in several preclinical models. METHODS: We performed a high throughput luciferase reporter screen using the NCI Diversity Set II to identify TRAIL-inducing compounds. RESULTS: Small molecule-mediated induction of TRAIL reporter activity was relatively modest and the majority of the hit compounds induced low levels of TRAIL upregulation. Among the candidate TRAIL-inducing compounds, TIC9 and ONC201/TIC10 induced sustained TRAIL upregulation and apoptosis in tumor cells in vitro and in vivo. However, ONC201/TIC10 potentiated tumor cell death while sparing normal cells, unlike TIC9, and lacked genotoxicity in normal fibroblasts. Investigating the effects of TRAIL-inducing compounds on cell signaling pathways revealed that TIC9 and ONC201/TIC10, which are the most potent inducers of cell death, exclusively activate Foxo3a through inactivation of Akt/ERK to upregulate TRAIL and its pro-apoptotic death receptor DR5. CONCLUSION: These studies reveal the selective activity of ONC201/TIC10 that led to its selection as a lead compound for this novel class of antitumor agents and suggest that ONC201/TIC10 is a unique inducer of the TRAIL pathway through its concomitant regulation of the TRAIL ligand and its death receptor DR5. More... »

PAGES

99

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12943-015-0346-9

DOI

http://dx.doi.org/10.1186/s12943-015-0346-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1010405266

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25927855


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curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1186/s12943-015-0346-9'

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curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1186/s12943-015-0346-9'


 

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