|Title:||18β-Glycyrrhetinic acid derivatives induced mitochondrial-mediated apoptosis through reactive oxygen species-mediated p53 activation in NTUB1 cells||Authors:||Lin K.-W.
|Keywords:||18β-Glycyrrhetinic acid derivatives; Antioxidant; Cytotoxicity; p53; Synthesis||Issue Date:||2011||Journal Volume:||19||Journal Issue:||14||Start page/Pages:||4274-4285||Source:||Bioorganic and Medicinal Chemistry||Abstract:||
Twenty six 18β-glycyrrhetinic acid (GA) (1) derivatives 2-27 including twelve new GA derivatives 10, 11, 13-17, 21-25 were synthesized and evaluated for cytotoxicities against NTUB1 cells (human bladder cancer cell lines). seco-Compounds 9, 25, and 27 are the most potent compounds of this series, inhibiting cell growth of human NTUB1 cells with an IC 50 values of 2.34 ± 0.28, 4.76 ± 1.15, and 3.31 ± 0.61 μM, respectively. Exposure of NTUB1 to 25 for 24 h significantly increased the production of reactive oxygen species (ROS). Flow cytometric analysis exhibited that treatment of NTUB1 with 25 did not induce cell cycle arrest but accompanied by an increase of apoptotic cell death in a dose-dependant manner after 24 h. Mitochondrial membrane potential (MMP) decreased significantly in a dose-dependant manner when the NTUB1 cells were exposed to 25 for 24 h. Marked collapse of the MMP suggested that dysfunction of the mitochondria may be involved in the oxidative burst and apoptosis induced by 25. Western blot analysis shows that NTUB1 cells treated with 25 increased the level of p-p53 in a dose-dependant manner. Further, NAC treatment prevented p53 phosphorylation stimulated by 25. These results suggested that 25 induced a mitochondrial- mediated apoptosis in NTUB1 cells through activation of p53, which are mainly mediated ROS generated by 25. ? 2011 Elsevier Ltd. All rights reserved.
|ISSN:||0968-0896||DOI:||10.1016/j.bmc.2011.05.054||metadata.dc.subject.other:||alpha tocopherol; cisplatin; epigallocatechin gallate; genistein; glycyrrhetinic acid derivative; paclitaxel; pyrrolidine dithiocarbamate; reactive oxygen metabolite; amidation; apoptosis; article; carbon nuclear magnetic resonance; cell cycle arrest; cell death; cell growth; cell strain; cell strain NTUB1; cell viability; controlled study; drug cytotoxicity; drug potency; drug potentiation; drug structure; drug synthesis; esterification; flow cytometry; growth inhibition; human; human cell; IC 50; mitochondrial membrane potential; oxidation; protein phosphorylation; proton nuclear magnetic resonance; respiratory burst; Western blotting; Antineoplastic Agents; Apoptosis; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Glycyrrhetinic Acid; Humans; Membrane Potential, Mitochondrial; Mitochondria; Molecular Conformation; Reactive Oxygen Species; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured; Tumor Suppressor Protein p53
|Appears in Collections:||醫學系|
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