Identification and preclinical evaluation of the small molecule, NSC745887, for treating glioblastomas via suppressing DcR3-associated signaling pathways
| Autor: | Hsu Shan Huang, Tsung Chih Chen, Li Yun Fann, Jiann Fong Lee, Ying Chen, Kuo-Hsing Ma, Alexander T.H. Wu, Ahmed Atef Ahmed Ali, Heng Cheng Chu, Da Chen Chu, Shao-Ju Weng |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty Population Brain tumor [18F]-FDG Histological staining animal-PET 03 medical and health sciences 0302 clinical medicine Internal medicine medicine education education.field_of_study business.industry Naphtho [2 3-f]quinoxaline-7 12-dione Cell survival rate medicine.disease decoy receptor 3 (DcR3) 030104 developmental biology Apoptosis 030220 oncology & carcinogenesis Decoy receptor 3 Signal transduction business Glioblastoma Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Li-Yun Fann 1, 2, 6 , Ying Chen 1, 3 , Da-Chen Chu 2 , Shao-Ju Weng 3 , Heng-Cheng Chu 4 , Alexander T.H. Wu 5 , Jiann-Fong Lee 6 , Ahmed Atef Ahmed Ali 6 , Tsung-Chih Chen 6 , Hsu-Shan Huang 1, 3, 6 and Kuo-Hsing Ma 1, 3 1 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC 2 Department of Nursing and Department of Neurosurgery, Taipei City Hospital, Taipei, Taiwan, ROC 3 Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, ROC 4 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC 5 The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC 6 Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC Correspondence to: Kuo-Hsing Ma, email: kuohsing91@yahoo.com.tw Hsu-Shan Huang, email: huanghs99@tmu.edu.tw Keywords: Naphtho [2,3-f]quinoxaline-7,12-dione; decoy receptor 3 (DcR3); [ 18 F]-FDG; animal-PET Received: July 19, 2017 Accepted: December 11, 2017 Published: December 27, 2017 ABSTRACT The small-molecule naphtha [2,3-f]quinoxaline-7,12-dione (NSC745887) can effectively inhibit the proliferation of various cancers by trapping DNA-topoisomerase cleavage. The aim of this study was to elucidate cellular responses of NSC745887 in human glioblastoma multiforme (GBM, U118MG and U87MG cells) and investigate the underlying molecular mechanisms. NSC745887 reduced the cell survival rate and increased the sub-G 1 population in dose- and time-dependent manners in GBM cells. Moreover, NSC745887 increased expression of γH2AX and caused DNA fragmentation leading to DNA damage. Furthermore, Annexin V/propidium iodide and Br-dTP staining showed the apoptotic effect of NSC745887 in GBM cells. DNA repair proteins of ataxia-telangiectasia mutated (ATM), ATM and Rad3-related, and decoy receptor 3 also decreased with NSC745887 treatment. In addition, NSC745887 caused apoptosis by the caspase-8/9-caspase-3-poly(ADP-ribose) polymerase cascade. An in vivo study indicated that NSC745887 suppressed the [ 18 F]-FDG-specific uptake value in brain tumors. Histological staining also indicated a decrease in Ki-67 and increases in γH2AX and cleaved caspase-3 in the brain tumor area. These data provide preclinical evidence for NSC745887 as a potential new small molecule drug for managing glioblastomas. |
| Databáze: | OpenAIRE |
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