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Mol Cancer. 2015 May 1;14:99. doi: 10.1186/s12943-015-0346-9.

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

Author information

1
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. joshjea@gmail.com.
2
Current affiliation: Oncoceutics, Inc., Hummelstown, PA, USA. joshjea@gmail.com.
3
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. g.krigsfeld@gmail.com.
4
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. luveroni@gmail.com.
5
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. patrick.mayes@gmail.com.
6
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. david.dicker@fccc.edu.
7
Department of Medical Oncology and Molecular Therapeutics Program, Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Fox Chase Cancer Center, Philadelphia, 19111, PA, USA. david.dicker@fccc.edu.
8
Department of Pathology, Program in Molecular Biology and Genetics, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA. wug@karmanos.org.
9
Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. wafik.eldeiry@fccc.edu.
10
Department of Medical Oncology and Molecular Therapeutics Program, Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Fox Chase Cancer Center, Philadelphia, 19111, PA, USA. wafik.eldeiry@fccc.edu.

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.

PMID:
25927855
PMCID:
PMC4428111
DOI:
10.1186/s12943-015-0346-9
[Indexed for MEDLINE]
Free PMC Article

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