Combination Treatment with Arsenic Trioxide and Sulindac Induces Apoptosis of NCI-H157 Human Lung Carcinoma Cells via ROS Generation with Mitochondrial Dysfunction.
- Author:
Hak Ryul KIM
1
;
Sei Hoon YANG
;
Eun Taik JEONG
Author Information
- Publication Type:Original Article
- Keywords: Arsenic trioxide; Sulindac; Apoptosis
- MeSH: Acetylcysteine; Antioxidants; Apoptosis*; Arsenic*; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Cytochromes c; Cytosol; Glutathione; Humans*; Hydrogen Peroxide; Leukemia, Promyelocytic, Acute; Lung*; Membrane Potential, Mitochondrial; Peroxidase; Raphanus; Sulindac*
- From:Tuberculosis and Respiratory Diseases 2005;59(1):30-38
- CountryRepublic of Korea
- Language:Korean
- Abstract: BACKGROUND: Arsenic trioxide (As2O3) has been used to treat acute promyelocytic leukemia, and it induces apoptosis in a variety of solid tumor cell lines including non-small cell lung cancer cells. However, nonsteroidal anti- inflammatory drugs (NSAID) can enhance tumor response to chemotherapeutic drugs or radiation. It was previously demonstrated that a combination treatment with As2O3 and sulindac induces the apoptosis of NCI-H157 human lung carcinoma cells by activating the caspase cascade. This study aimed to determine if a combination treatment augmented its apoptotic potential through other pathways except for the activation of the caspase cascade. MATERIAL AND METHODS: The NCI-H157 cells were treated with As2O3, sulindac and antioxidants such as glutathione (GSH) and N-acetylcysteine (NAC). The cell viability was measured by a MTT assay, and the level of intracellular hydrogen peroxide (H2O2) generation was monitored fluorimetrically using a scopoletin-horse radish peroxidase (HRP) assay. Western blotting and mitochondrial membrane potential transition analysis were performed in order to define the mechanical basis of apoptosis. RESULTS: The viability of the cells was decreased by a combination treatment of As2O3 and sulindac, and the cells were protected using antioxidants in a dose-dependent manner. The increased H2O2 generation by the combination treatment was inhibited by antioxidants. The combination treatment induced changes in the mitochondrial tran-smembrane potential as well as the expression of the Bcl-2 family proteins, and increased cytochrome c release into the cytosol. However, the antioxidants inhibited the effects of the combination treatment. CONCLUSION: Combination treatment with As2O3 and sulindac induces apoptosis in NCI-H157 human lung carcinoma cells via ROS generation with a mitochondrial dysfunction.
