title: Inhibition of c-Myc by 10058-F4 induces growth arrest and chemosensitivity in pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a formidable medical challenge due to its malignancies and the absence of effective treatment. c-Myc, as an important transcription factor, plays crucial roles in cell cycle progression, apoptosis and cellular transformation. The c-Myc inhibitor, 10058-F4, has been reported act as a tumor suppressor in several different tumors. In current study, the tumor-suppressive roles of 10058-F4 was observed in human pancreatic cancer cells in vitro as demonstrated by decreased cell viability, cell cycle arrest at the G1/S transition and increased caspase3/7 activity. And tumor responses to gemcitabine were also significantly enhanced by 10058-F4 in PANC-1 and SW1990 cells. In a subcutaneous xenograft model, however, 10058-F4 showed no significant influence on pancreatic tumorigenesis. When combined with gemcitabine, tumorigenesis was drastically attenuated compared with gemcitabine group or 10058-F4 group; this synergistic effect was accompanied with decreased PCNA-positive cells and reduced TUNEL-positive cells in the combined treated group. Subsequent studies revealed that decreased glycolysis may be involved in the inhibitory effect of 10058-F4 on PDAC. Taken together, this study demonstrates the roles of 10058-F4 in PDAC and provides evidence that 10058-F4 in combination with gemcitabine showed significant clinical benefit over the usage of gemcitabine alone.
authors.affiliation: Department of hepatobiliary surgery, The Fourth Hospital of Hebei Medical University, 050011 Shijiazhuang, P.R. China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Jiankang Road, 050011 Shijiazhuang, P.R. China. Electronic address: olivefhy@sina.com.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Fan
authors.affiliation: Department of hepatobiliary surgery, The Fourth Hospital of Hebei Medical University, 050011 Shijiazhuang, P.R. China.
authors.forename: Sheng-Chao
authors.initials: SC
authors.lastname: Li
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; D006131:Growth Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D013844:Thiazoles
keywords: Chemosensitivity; Growth; Pancreatic ductal adenocarcinoma; c-Myc