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Biochem Biophys Res Commun. 2016 Aug 5;476(4):260-266. doi: 10.1016/j.bbrc.2016.05.106. Epub 2016 May 24.

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

Author information

1
Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China.
2
Department of Anesthesiology, Yidu Central Hospital, Weifang Medical University, Qingzhou, China. Electronic address: wanghongqiruyy@sina.com.
3
Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China. Electronic address: jiangyishengvv@163.com.

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.

KEYWORDS:

Akt-Erk signaling; Chemosensitization; Gemcitabine; Pancreatic cancer; TIC10; TRAIL

PMID:
27233611
DOI:
10.1016/j.bbrc.2016.05.106
[Indexed for MEDLINE]

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