title: 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.affiliation: Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Qiangbo
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Yidu Central Hospital, Weifang Medical University, Qingzhou, China. Electronic address: wanghongqiruyy@sina.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ran
authors.affiliation: Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Zongli
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China. Electronic address: jiangyishengvv@163.com.
authors.forename: Runde
authors.initials: R
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use*; D007093:Imidazoles; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016513:Mice, SCID; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C585684:TIC10 compound; D051057:Proto-Oncogene Proteins c-akt; D053181:Caspase 8; D053453:Caspase 9
keywords: Akt-Erk signaling; Chemosensitization; Gemcitabine; Pancreatic cancer; TIC10; TRAIL