Abstract |
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.
|
Authors | Xin Liang, Yufang Xu, Ke Xu, Jianwen Liu, Xuhong Qian |
Journal | Molecular cancer research : MCR
(Mol Cancer Res)
Vol. 8
Issue 12
Pg. 1619-32
(Dec 2010)
ISSN: 1557-3125 [Electronic] United States |
PMID | 21076048
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | ©2010 AACR. |
Chemical References |
- 14-3-3 Proteins
- Antineoplastic Agents
- Benzothiazoles
- DNA-Binding Proteins
- MBD2 protein, human
- N-(2-(dimethylamino)ethyl)-2-aminothiazonaphthalimide
- Naphthalimides
- Organophosphonates
- Proto-Oncogene Proteins c-bcl-2
- RNA, Small Interfering
- amonafide
- Adenine
|
Topics |
- 14-3-3 Proteins
(genetics, metabolism)
- Adenine
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Benzothiazoles
(pharmacology)
- Cell Line, Tumor
- DNA-Binding Proteins
(biosynthesis, genetics, metabolism)
- Down-Regulation
(genetics)
- Drug Resistance, Neoplasm
- Gene Knockdown Techniques
- Genes, MDR
- Genes, bcl-2
(drug effects)
- Genes, p53
(drug effects)
- HL-60 Cells
- Humans
- K562 Cells
- Leukemia, Promyelocytic, Acute
(drug therapy, genetics, metabolism)
- Naphthalimides
(chemistry, pharmacology)
- Organophosphonates
- Proto-Oncogene Proteins c-bcl-2
(biosynthesis, deficiency, genetics, metabolism)
- RNA, Small Interfering
(genetics)
- U937 Cells
|