title: DYT-40, a novel synthetic 2-styryl-5-nitroimidazole derivative, blocks malignant glioblastoma growth and invasion by inhibiting AEG-1 and NF-κB signaling pathways.
abstract: Astrocyte elevated gene-1 (AEG-1) has been explored as a novel target for human glioma therapy, thus reflecting its potential contribution to gliomagenesis. In the present study, we investigated the effect of DYT-40, a novel synthetic 2-styryl-5-nitroimidazole derivative, on cell growth and invasion in glioblastoma (GBM) and uncovered the underlying mechanisms of this molecule. DYT-40 induces the intrinsic mitochondrial pathway of apoptosis and inhibits the epithelial-mesenchymal transition (EMT) and invasion of GBM cell lines. Furthermore, DYT-40 deactivates PI3K/Akt and MAPK pathways, suppresses AEG-1 expression, and inhibits NF-κB nuclear translocation. DYT-40 reduced the tumor volumes in a rat C6 glioma model by apoptotic induction. Moreover, HE staining demonstrated that the glioma rat model treated with DYT-40 exhibited better defined tumor margins and fewer invasive cells to the contralateral striatum compared with the vehicle control and temozolomide-treated rats. Microscopic examination showed a decrease in AEG-1-positive cells in DYT-40-treated rats compared with the untreated controls. DYT-40-treatment increases the in vivo apoptotic response of glioma cells to DYT-40 treatment by TUNEL staining. In conclusion, the inhibitory effects of DYT-40 on growth and invasion in GBM suggest that DYT-40 might be a potential AEG-1 inhibitor to prevent the growth and motility of malignant glioma.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China.|State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xuguan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Ou
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
authors.forename: Zhongchang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases; Department of oral and maxillofacial surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Breast Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China.|State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins; D008853:Microscopy; D016328:NF-kappa B / Q000378:metabolism*; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D016601:RNA-Binding Proteins; D051381:Rats; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: C000593702:2-styryl-5-nitroimidazole; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D016328:NF-kappa B; D009593:Nitroimidazoles; D016601:RNA-Binding Proteins