The preclinical evaluation of TIC10/ONC201 as an anti-pancreatic cancer agent.

Abstract

Here we evaluated the potential anti-pancreatic cancer activity by TIC10/ONC201, a first-in-class small-molecule inducer of tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL). The in vitro results showed that TIC10 induced potent cytotoxic and cytostatic activities in several human pancreatic cancer cell lines (Panc-1, Mia-PaCa2, AsPC-1 or L3.6). TIC10 activated both extrinsic (TRAIL-caspase-8-dependent) and endogenous/mitochondrial (caspase-9-dependent) apoptosis pathways in the pancreatic cancer cells. Molecularly, we showed that TIC10 inhibited Akt-Erk activation, yet induced TRAIL expression in pancreatic cancer cells. Significantly, TIC10, at a relatively low concentration, sensitized gemcitabine-induced growth inhibition and apoptosis against pancreatic cancer cells. Further, TIC10 and gemcitabine synergistically inhibited Panc-1 xenograft growth in SCID mice. The combination treatment also significantly improved mice survival. In addition, Akt-Erk in-activation and TRAIL/cleaved-caspase-8 induction were observed in TIC10-treated Panc-1 xenografts. Together, the preclinical results of the study demonstrate the potent anti-pancreatic cancer activity by TIC10, or with gemcitabine.

• Authors: Qiangbo Zhang, Hong Wang, Lin Ran, Zongli Zhang, Runde Jiang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 476 Issue 4 Pg. 260-266 (08 05 2016) ISSN: 1090-2104 [Electronic] United States
• PMID: 27233611 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Heterocyclic Compounds, 4 or More Rings
• Imidazoles
• Pyridines
• Pyrimidines
• RNA, Messenger
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• TIC10 compound
• Proto-Oncogene Proteins c-akt
• Caspase 8
• Caspase 9

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Caspase 8 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme Activation (drug effects)
• Female
• Heterocyclic Compounds, 4 or More Rings (pharmacology, therapeutic use)
• Imidazoles
• MAP Kinase Signaling System (drug effects)
• Mice, SCID
• Pancreas (drug effects, metabolism, pathology)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridines
• Pyrimidines
• RNA, Messenger (genetics)
• Signal Transduction (drug effects)
• TNF-Related Apoptosis-Inducing Ligand (genetics)
• Up-Regulation (drug effects)