title: 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.
authors.affiliation: State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liang
authors.forename: Yufang
authors.initials: Y
authors.lastname: Xu
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.forename: Jianwen
authors.initials: J
authors.lastname: Liu
authors.forename: Xuhong
authors.initials: X
authors.lastname: Qian
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000225:Adenine; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D019450:Genes, MDR; D019254:Genes, bcl-2 / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D053644:Naphthalimides / Q000737:chemistry / Q000494:pharmacology*; D063065:Organophosphonates; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020298:U937 Cells
chemical_list: D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D004268:DNA-Binding Proteins; C489325:MBD2 protein, human; C556398:N-(2-(dimethylamino)ethyl)-2-aminothiazonaphthalimide; D053644:Naphthalimides; D063065:Organophosphonates; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C037020:amonafide; D000225:Adenine