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B1, a novel amonafide analogue, overcomes the resistance conferred by Bcl-2 in human promyelocytic leukemia HL60 cells.

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.
AuthorsXin Liang, Yufang Xu, Ke Xu, Jianwen Liu, Xuhong Qian
JournalMolecular cancer research : MCR (Mol Cancer Res) Vol. 8 Issue 12 Pg. 1619-32 (Dec 2010) ISSN: 1557-3125 [Electronic] United States
PMID21076048 (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

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