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|標題:||Novel Quinazoline HMJ-30 Induces U-2 OS Human Osteogenic Sarcoma Cell Apoptosis through Induction of Oxidative Stress and Up-Regulation of ATM/p53 Signaling Pathway||作者:||Chiu, Y.J.
|關鍵字:||HMJ-30;human osteogenic sarcoma U-2 OS cells;apoptosis;ATM;p53;mitochondria-dependent pathways;cancer;osteosarcoma;agents;p53;dna;atm;autophosphorylation;chemotherapy;inhibition||Project:||Journal of Orthopaedic Research||期刊/報告no：:||Journal of Orthopaedic Research, Volume 29, Issue 9, Page(s) 1448-1456.||摘要:||
Human osteogenic sarcoma is the most common primary bone tumor. Despite of the success of frontline therapy, about 40% of patients have disease progression and further therapy is palliative and toxic. In this study, we developed a novel quinazoline HMJ-30 to investigate the cell growth inhibition and apoptotic responses in U-2 OS human osteogenic sarcoma cells. Our results demonstrated that HMJ-30 significantly reduced cell viabilities of U-2 OS, HOS, and 143B cells in a dose-dependent manner, but it exhibited low cytotoxicity in normal hFOB cells. HMJ-30 induced DNA damage and apoptosis in U-2 OS cells as revealed by morphologic changes, comet assay and DAPI staining. Immuno-staining, colorimetric assays, and Western blotting analyses indicated that activities of caspase-8, caspase-9, and caspase-3 and the levels of Bcl-2 family-related proteins (Bcl-2, Mcl-1, Bax, BAD, and t-Bid) were altered in HMJ-30-treated U-2 OS cells. Pretreatment of cells with caspase-8, -9, and -3 specific inhibitors significantly reduced the cell growth inhibition. HMJ-30-induced apoptosis was mediated through both death-receptor and mitochondria-dependent apoptotic pathways in U-2 OS cells. HMJ-30 induced early phosphorylation of p53(Ser18) was through the activation of ataxia telangiectasia mutated (ATM) in U-2 OS cells. The cell growth inhibition by HMJ-30 was substantially attenuated either by the pre-incubation of U-2 OS cells with N-acetylcysteine (NAC, an antioxidant) and caffeine (an ATM kinase inhibitor) or by p53 knockdown via RNAi. In conclusion, ROS dependent-ATM/p53 signaling pathway is involved in HMJ-30-induced apoptosis in U-2 OS cells. (C) 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29: 1448-1456, 2011
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