B1, a novel amonafide analogue, overcomes the resistance conferred by Bcl-2 in human promyelocytic leukemia HL60 cells.
In the course of screening for novel anticancer compounds, B1 [N-(2-(dimethylamino)ethyl)-2-aminothiazonaphthalimide], a novel amonafide analogue, was generated as a new anticancer candidate. In the present study, B1 displayed stronger antitumor effects than amonafide in HL60 cells. We further examined whether B1 overcomes the resistance conferred by Bcl-2, as overcoming the ... resistance conferred by Bcl-2 represents an attractive therapeutic strategy against cancer. Our viability assay showed that B1 overcomes the resistance conferred by Bcl-2 in human promyelocytic leukemia HL60 cells. Various apoptosis assessment assays showed that B1 overcomes the resistance conferred by Bcl-2 in HL60 cells by inducing apoptosis. Noticeably, we elucidated the marked downregulation of 14-3-3σ protein by B1, indicating that B1 overcomes the resistance conferred by Bcl-2 in HL60 cells via 14-3-3σ. The analysis of chromatin immunoprecipitation assay indicated that MBD2 was associated with the methylated 14-3-3σ promoter-associated CpG island and thus interfered with transcriptional activity of the methylated promoter. Furthermore, knockdown of MBD2, using siRNA transfection, inhibited B1-induced apoptosis and overcame the resistance conferred by Bcl-2. Accordingly, these data showed the involvement of MBD2 in B1-induced apoptosis and overcoming the resistance conferred by Bcl-2, which suggested that MBD2 might guide the development of future anticancer agents.
Mesh Terms:
14-3-3 Proteins, Antineoplastic Agents, Apoptosis, Benzothiazoles, Cell Line, Tumor, DNA-Binding Proteins, Down-Regulation, Drug Resistance, Neoplasm, Gene Knockdown Techniques, Genes, MDR, Genes, bcl-2, Genes, p53, HL-60 Cells, Humans, K562 Cells, Leukemia, Promyelocytic, Acute, Naphthalimides, Proto-Oncogene Proteins c-bcl-2, RNA, Small Interfering, U937 Cells
14-3-3 Proteins, Antineoplastic Agents, Apoptosis, Benzothiazoles, Cell Line, Tumor, DNA-Binding Proteins, Down-Regulation, Drug Resistance, Neoplasm, Gene Knockdown Techniques, Genes, MDR, Genes, bcl-2, Genes, p53, HL-60 Cells, Humans, K562 Cells, Leukemia, Promyelocytic, Acute, Naphthalimides, Proto-Oncogene Proteins c-bcl-2, RNA, Small Interfering, U937 Cells
Mol. Cancer Res.
Date: Dec. 01, 2010
PubMed ID: 21076048
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