R16, a novel amonafide analogue, induces apoptosis and G(2)-M arrest via poisoning topoisomerase II

doi:10.1158/1535-7163.MCT-06-0584

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	R16, a novel amonafide analogue, induces apoptosis and G(2)-M arrest via poisoning topoisomerase II
	Zhu, Hong ; Huang, Min; Yang, Fan ; Chen, Yi; Miao, Ze-Hong ; Qian, Xu-Hong ; Xu, Yu-Fang ; Qin, Yu-Xin ; Luo, Hai-Bin ; Shen, Xu
刊名	MOLECULAR CANCER THERAPEUTICS
	2007-02
卷号	6 期号:2 页码:484-495
ISSN号	1535-7163
DOI	10.1158/1535-7163.MCT-06-0584
文献子类	Article
英文摘要	Amonafide, a naphthalimide derivative, although selected for exploratory clinical trials for its potent anticancer activity, has long been challenged by its unpredictable side effects. In the present study, a novel amonafide analogue, 2-(2-dimethylamino)-6-thia-2-aza-benzo-[def]-chrysene-1,3-diones (R16) was synthesized by substituting 5'-NH2 of the naphthyl with a heterocyclic group to amonafide, with additional introduction of a thiol group. In a panel of various human tumor cell lines, R16 was more cytotoxic than its parent compound amonafide. It was also effective against multidrug-resistant cells. Importantly, the i.p. administration of R16 inhibited tumor growth in mice implanted with S-180 sarcoma and H-22 hepatoma. The molecular and cellular machinery studies showed that the R16 functions as a topoisomerase II (topo II) poison via binding to the ATPase domain of human topo II alpha. The superior cytotoxicity of R16 to amonafide was ascribed to its potent effects on trapping topo II-DNA cleavage complexes. Moreover, using a topo II catalytic inhibitor aclarubicin, ataxia-telangiectasia-mutated (ATM)/ATM and Rad3-related (ATR) kinase inhibitor caffeine and topo II-deficient HL-60/MX2 cells, we further showed that R16-triggered DNA double-strand breaks, tumor cell cycle arrest, and apoptosis were in a topo II-dependent manner. Taken together, R16 stood out by its improved anticancer activity, appreciable anti-multidrug resistance activities, and well-defined topo II poisoning mechanisms, as comparable with the parent compound amonafide. All these collectively promise the potential value of R16 as an anticancer drug candidate, which deserves further development.
WOS关键词	CYTOCHROME-C RELEASE ; ADVANCED BREAST-CANCER ; LEUKEMIA GROUP-B ; ACETYLATOR PHENOTYPE ; CELL-DEATH ; DNA TOPOISOMERASES ; HL-60 CELLS ; ANTITUMOR ; CYTOTOXICITY ; INHIBITION
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000244262700009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273342]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Ding, Jian
作者单位	1.E China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China 2.Chinese Acad Sci, Div Anti Tumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Ocean Univ China, Dept Pharmacol & Glycobiol, Marine Drug & Food Inst, Qingdao, Peoples R China
推荐引用方式 GB/T 7714	Zhu, Hong,Huang, Min,Yang, Fan,et al. R16, a novel amonafide analogue, induces apoptosis and G(2)-M arrest via poisoning topoisomerase II[J]. MOLECULAR CANCER THERAPEUTICS,2007,6(2):484-495.
APA	Zhu, Hong.,Huang, Min.,Yang, Fan.,Chen, Yi.,Miao, Ze-Hong.,...&Ding, Jian.(2007).R16, a novel amonafide analogue, induces apoptosis and G(2)-M arrest via poisoning topoisomerase II.MOLECULAR CANCER THERAPEUTICS,6(2),484-495.
MLA	Zhu, Hong,et al."R16, a novel amonafide analogue, induces apoptosis and G(2)-M arrest via poisoning topoisomerase II".MOLECULAR CANCER THERAPEUTICS 6.2(2007):484-495.