The development of a novel therapy for malignant glioma is a vigorous area in both chemistry and cancer research. Previously, we reported that the small molecule naphtho [2, 3-f] quinoxaline-7, 12-dione (CC12) effectively inhibits the proliferation of several cancers. In this study, we further investigated the therapeutic effects of CC12 on human glioblastoma (GBM) cells and clarified underlying mechanisms of these effects.
Human GBM cell lines, U118MG and U87MG, were used for in vitro and in vivo. Analysis of CC12 effects on cell cycle and apoptosis, while nude mice bearing xenograft of the tumor cells were used for in-vivo analysis of CC12 effects on tumor metabolism and size by using animal positron emission tomography (PET). DNA fragmentation, mitochondrial membrane potential change, cell cycle inhibiion and apoptosis were labelled with fluorescent tracers or antibodies, and followed by measured with flow cytometry. Apoptotic-associated proteins were quantified by immunoblot analysis. Tumors in animals were labelled with [18F]-fluorodeoxyglucose ([18F]-FDG), and imaged by animal-PET. Tumor tissue was collected and weighed, and vital organs including the heart, kidneys and liver were extracted for hematoxylin and eosin staining.
We found that CC12 induced cell cycle arrest as GBM cells were accumulated in the subG1 and G2/M phases in a dose- and time-dependent manner. This effect was caused by DNA damage response in GBM cells. Moreover, the treatment of CC12 reduced the expression of decoy receptor 3 and disrupted the mitochondrial membrane signaling cascade in GBM cells, leading to apoptosis of the cells. In the heterotopic mice model, we found that the size of the GBM cell xenografts was decreased following the treatment of CC12, indicated by [18F]-FDG coupled with PET.
These findings provide evidence from molecular, cellular, and physiological levels that strongly suggest that CC12 is a promising small-molecule agent for human GBM.
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