Abstract | AIM: The cytotoxic activities of a series of bis-aziridinylnaphthoquinone, AZ1 to AZ4, on human lung carcinoma cell lines, H460, and normal lung cells fibroblast cell line, MRC-5, and the mechanisms of H460 cells induced by AZ4 were investigated. METHODS: The MTT assay was used to determine the cell proliferation. Cell cycle was analysed by FACS. The activity of caspase 3, 8 and 9 was determined by cell-permeable fluorogenic detection system. Western blot assay was used to evaluate the regulation of cyclin B, Cdc-2, p53, p21, and the Bcl-2 protein. RESULTS: AZ1 to AZ4 displayed various cytotoxicity activities against H460 and MRC-5 cells. Compared to those compounds, AZ4 was with the most effective agent among the 5 tested analogues at reducing H460 cell viability with an IC(50) value of 1.23 micromol/L; it also exhibited weak cytotoxicity against MRC-5 cells with an IC(50) value of 12.7 micromol/L. The results show that growth arrest on the G2-M phase of H460 cells induced by AZ4 for 24 h was discovered, and this might be altered with the reduced Cdc-2 protein expression of 47% at 2.0 micromol/L AZ4, but not with cyclin B protein expression. The AZ4 treated cells were then led to apoptosis after 48 h. This was associated with the activation of apoptotic enzyme caspase 3 and mediated by caspase 8, but not caspase 9 at various concentrations of AZ4 after being cultured for 48 h and 30 h, respectively. The anti-apoptotic protein (Bcl-2) expression in H460 cells altered by 39% with downregulation, and the p53 protein by 25% with upregulation after being cultured with 2.0 micromol/L AZ4 for 48 h. In a time-dependent manner, the expression of the p53 and p21 proteins were increased to the maximum at 24 h, and then decreased at 48. CONCLUSION: AZ4 represents a novel antitumor aziridinylnaphthoquinone with therapeutic potential against the non-small cell lung cancer cells.
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Authors | Kou-gea Shyu, Sheng-tung Huang, Hsien-shou Kuo, Wen-pin Cheng, Yuh-ling Lin |
Journal | Acta pharmacologica Sinica
(Acta Pharmacol Sin)
Vol. 28
Issue 4
Pg. 559-66
(Apr 2007)
ISSN: 1671-4083 [Print] United States |
PMID | 17376296
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents
- Naphthoquinones
- Proto-Oncogene Proteins c-bcl-2
- Tumor Suppressor Protein p53
- bis-aziridinylnaphthoquinone
- Caspases
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Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Carcinoma, Non-Small-Cell Lung
(drug therapy, pathology)
- Caspases
(biosynthesis)
- Cell Cycle
(drug effects)
- Cell Line, Tumor
- G2 Phase
(drug effects)
- Humans
- Lung Neoplasms
(drug therapy, pathology)
- Naphthoquinones
(pharmacology)
- Proto-Oncogene Proteins c-bcl-2
(biosynthesis, genetics)
- Tumor Suppressor Protein p53
(biosynthesis, genetics)
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