Abstract
Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an antitumor protein that is in clinical trials as a potential anticancer therapy but suffers from drug properties that may limit efficacy such as short serum half-life, stability, cost, and biodistribution, particularly with respect to the brain. To overcome such limitations, we identified TRAIL-inducing compound 10 (TIC10), a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. TIC10 inactivates kinases Akt and extracellular signal-regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Apoptosis / genetics
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Bystander Effect / drug effects
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Cell Death / drug effects
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Cell Line, Tumor
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism*
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Enzyme Activation / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Forkhead Box Protein O3
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Forkhead Transcription Factors / metabolism*
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Gene Expression Regulation, Neoplastic / drug effects
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Glioblastoma / drug therapy
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Glioblastoma / enzymology
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Glioblastoma / genetics
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Glioblastoma / pathology
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology*
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Heterocyclic Compounds, 4 or More Rings / therapeutic use
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Humans
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Imidazoles
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Mice
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Models, Biological
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Protein Transport / drug effects
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Protein Transport / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Pyridines
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Pyrimidines
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Signal Transduction / drug effects
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Signal Transduction / genetics
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TNF-Related Apoptosis-Inducing Ligand / genetics*
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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Transcriptional Activation*
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Up-Regulation / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Heterocyclic Compounds, 4 or More Rings
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Imidazoles
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Pyridines
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Pyrimidines
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TNF-Related Apoptosis-Inducing Ligand
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TIC10 compound
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases