Abstract
BackgroundRecent studies showed that benzimidazoleisoquinolinone derivatives exhibit anticancer activity against human cancer cell lines. The aim of this study is to evaluate the anti-tumor effects and mechanisms of benzimidazoleisoquinolinones in isocitrate dehydrogenase-wildtype subtype of human glioblastoma (GBM) cells.MethodsHuman U87 and LN229 cell lines were used to perform the experiments. MTT was applied to screen the effective small molecular inhibitors suppressing growth of GBM cells. Colony formation and BrdU staining assays were performed to assess the inhibition effect of compound-1H on the proliferation of GBM cells. The cell cycle and apoptosis were measured by flow cytometry and western blot to analyze the changes of the relative protein expressions and their signal pathways.ResultsCompound-1H could suppress GBM cells in a time- and dose-dependent manner. Treatment of compound-1H could arrest cell cycle in S phase through up-regulating P21 and P53, and down-regulating cyclin A and E in a dose-dependent manner. Compound-1H also induced mitochondrial-dependent apoptosis by increasing Bax, cleaved caspase-3, cleaved caspase-9 and poly ADP-ribose polymerase expression, and decreasing Bcl-2 expression. Moreover, phosphorylated (p)-AKT and p-ERK levels relating to cell proliferation were dramatically decreased in U87 and LN229 cells.ConclusionsOur results suggest that it is the first time to report the compound-1H with benzimidazoleisoquinolinone core playing antitumor activity in human glioblastoma cells by inhibiting Raf/MEK/ERK and PI3K/AKT signaling pathways, and it could be as a lead compound for the further development of targeted glioblastoma cancer therapy.
Highlights
Recent studies showed that benzimidazoleisoquinolinone derivatives exhibit anticancer activity against human cancer cell lines
Soft agar assay was performed to evaluate the effect of the compound-1H in colony formation, and the results demonstrated that smaller and lesser colonies were formed in treated groups (15, 30 and 60 μmol/L) compared with control groups in both glioblastoma cell lines (Fig. 2c)
The Q4, Q3 and Q2 quadrants represent the populations of normal, early apoptotic and late apoptotic cells, respectively. b Percentages of surviving cells, early and late apoptotic cells are shown as the mean ± standard deviation (SD) (n = 3). c Apoptotic nuclear morphological changes induced by compound-1H (0, 15, 30, 60 μmol/L) for 48 h were observed using Hoechst 33342 staining in U87 and LN229 cells
Summary
Recent studies showed that benzimidazoleisoquinolinone derivatives exhibit anticancer activity against human cancer cell lines. The aim of this study is to evaluate the anti-tumor effects and mechanisms of benzi‐ midazoleisoquinolinones in isocitrate dehydrogenase-wildtype subtype of human glioblastoma (GBM) cells. Glioblastoma (GBM), which exhibits rapid cellular proliferation, diffuse metastasis and extensive angiogenesis, is the most highly aggressive type of brain tumors in adults [1]. The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ ERK) signaling pathway is often abnormally activated in various tumors including glioblastoma, and has become an attractive target for the development of novel antineoplastic drugs [8,9,10]. The discovery of potential anticancer agents, which have better bioactivities in inducing apoptosis through the deactivation of MAPK/ERK signaling pathway in glioblastoma cells, seems to be an effective strategy for the drug discovery in glioblastoma research [11, 12]
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