ONTD induces apoptosis of human hepatoma Bel-7402 cells via a MAPK-dependent mitochondrial pathway and the depletion of intracellular glutathione
| Autor: | Linna Wang, Tan Jiani, Hui Ji, Zhonghui Lai, Meiyu Chen, Yisheng Lai, Jun Zha, Wenyan Long, Ling Liu, Tong Chen |
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| Rok vydání: | 2013 |
| Předmět: |
Male
MAPK/ERK pathway Carcinoma Hepatocellular Cell Survival MAP Kinase Signaling System p38 mitogen-activated protein kinases Intracellular Space Apoptosis Mitochondrion Biology Mitochondrial Membrane Transport Proteins Biochemistry Antioxidants Mice Cell Line Tumor Cyclosporin a Animals Humans Cell Shape Cell Proliferation Mice Inbred ICR Cell Death Mitochondrial Permeability Transition Pore Kinase Body Weight Liver Neoplasms Cell Biology Glutathione Molecular biology Triterpenes Mitochondria Cell biology Mitochondrial permeability transition pore Reactive Oxygen Species Intracellular |
| Zdroj: | The International Journal of Biochemistry & Cell Biology. 45:2632-2642 |
| ISSN: | 1357-2725 |
| DOI: | 10.1016/j.biocel.2013.08.021 |
| Popis: | 3-Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile (ONTD) is a novel synthetic derivative of glycyrrhetinic acid (GA), which has the ability to inhibit the proliferation of human hepatocellular carcinoma (HCC) cells. However, the mechanisms by which ONTD exerts its inhibitory effects remain elusive. The present study was conducted to investigate the cytotoxicity of ONTD in Bel-7402 cells and its molecular mechanisms. We found that ONTD depleted intracellular GSH, increased the level of ROS, and consequently induced mitochondrial permeability transition (MPT) leading to the release of apoptosis-inducing factor (AIF) and cytochrome c (Cyt c) to the cytosol. Mitochondrial alteration and subsequent apoptotic cell death in ONTD-treated Bel-7402 cells could be blocked by addition of exogenous antioxidants N-acetylcystein (NAC), GSH and the MTP inhibitor cyclosporin A (CsA). In addition, ONTD activated the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPK) but not extracellular signal-regulated protein kinases (ERK 1/2). When the cells were exposed to SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), the deregulation of the expression of apoptotic proteins was attenuated. Furthermore, 40 mg/kg ONTD significantly reduced tumor weight (-70.62%, p0.01) in the H22 tumor-bearing mouse model in vivo. Taken together, these findings provide the first experimental evidence supporting that ONTD could induce apoptosis of Bel-7402 cells via MAPK-mediated mitochondrial pathway and ONTD has the potential to be developed as a therapeutic agent for the treatment of HCC. |
| Databáze: | OpenAIRE |
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