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.
Highlights
Malignant gliomas, such as glioblastoma multiforme (GBM) and anaplastic astrocytomas (AA), are the most common primary brain tumors[1]
Previous studies have demonstrated that the ectopic over-expression of Astrocyte elevated gene-1 (AEG-1) promoted epithelial-mesenchymal transition (EMT), which resulted from the down-regulation of E-cadherin and the up-regulation of vimentin in lung cancer cell lines and clinical lung cancer specimens[13]
Ras activation initiates a complex axis of transduction, including the Raf/MAPK (ERK) pathway, originally involved in the plasma membrane-to-nucleus signaling crucial for cell mitogen-mediated proliferation[14] and the phosphatidylinositol 3-kinase (PI3K) Akt pathway, which is involved in cell survival signaling[15]
Summary
Malignant gliomas, such as glioblastoma multiforme (GBM) and anaplastic astrocytomas (AA), are the most common primary brain tumors[1]. Previous studies have demonstrated that the ectopic over-expression of AEG-1 promoted epithelial-mesenchymal transition (EMT), which resulted from the down-regulation of E-cadherin and the up-regulation of vimentin in lung cancer cell lines and clinical lung cancer specimens[13]. In these contexts, AEG-1 might provide a viable target for clinical therapeutic intervention in the EMT-mediated invasion of carcinomas. Previous studies have shown that AEG-1 is an important positive regulator of nuclear factor kappa-B p65 (NF-κB) and that the activation of NF-κBp65, which is induced by AEG-1, exhibits a key molecular mechanism in which AEG-1 promotes cell growth and invasion in malignant glioma cells[8,21]. 3p showed the most potent activity in vitro which inhibited the growth of adenocarcinomic human alveolar basal epithelial cells A549 with IC50 value of 3.11 μMand human cervical cancer cells Hela with IC50 value of 2.54 μM respectively, the efficacy of DYT-40 on glioma cells growth seems to be better than 3p
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
