Identification and preclinical evaluation of the small molecule, NSC745887, for treating glioblastomas via suppressing DcR3- associated signaling pathways

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-G1 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 [18F]-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.