title: 2-Triazenoazaindoles: α novel class of triazenes inducing transcriptional down-regulation of EGFR and HER-2 in human pancreatic cancer cells.
abstract: Pancreatic cancer is a complex malignancy arising from the accumulation             of genetic and epigenetic defects in the affected cells. Standard chemotherapy             for patients with advanced disease shows only modest effects and is associated             with considerable toxicity. Overexpression or aberrant activation of members of             the epidermal growth factor receptor tyrosine kinase family, which includes EGFR             and HER-2, occurs frequently and is associated with multiple drug resistance and             decreased patient survival. In this study, we have investigated the therapeutic             potential of AS104, a novel compound of the triazene class, with potential inhibitory             effects on EGFR. We found that treatment of cells with AS104 causes significant             reduction of cell growth and metabolic activity in four human pancreatic cancer             cell lines. Furthermore, we show that the AS104-mediated induction of apoptotic             cell death is associated with stimulation of autophagy in a dose-dependent manner.             Treatment of cells with AS104 results in significant down-regulation of EGFR and             HER-2 expression and activity and subsequent inhibition of downstream signaling             proteins. Quantitative RT-PCR analysis and assays with proteasome inhibitors revealed             that AS104 regulates the expression of EGFR and HER-2 at the transcriptional level.             These findings provide for the first time experimental evidence for efficacy of             AS104 in the simultaneous transcriptional repression of EGFR and HER-2 genes and             suggest that AS104 may have therapeutic potential in the treatment of pancreatic             cancers that express high levels of the aforementioned receptor tyrosine kinases.
authors.affiliation: Department of Biochemistry and Molecular Biology, University                     of Southern Denmark, Odense, Denmark.
authors.forename: Jan N
authors.initials: JN
authors.lastname: Kreutzer
authors.forename: Alessia
authors.initials: A
authors.lastname: Salvador
authors.forename: Patrizia
authors.initials: P
authors.lastname: Diana
authors.forename: Girolamo
authors.initials: G
authors.lastname: Cirrincione
authors.forename: Daniela
authors.initials: D
authors.lastname: Vedaldi
authors.forename: David W
authors.initials: DW
authors.lastname: Litchfield
authors.forename: Olaf-Georg
authors.initials: OG
authors.lastname: Issinger
authors.forename: Barbara
authors.initials: B
authors.lastname: Guerra
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D014226:Triazenes / Q000494:pharmacology*
chemical_list: D066246:ErbB Receptors; D007211:Indoles; D018719:Erb-b2 Receptor Tyrosine Kinases; D014226:Triazenes