MFTZ-1, an actinomycetes subspecies-derived antitumor macrolide, functions as a novel topoisomerase II poison

doi:10.1158/1535-7163.MCT-07-0014

	MFTZ-1, an actinomycetes subspecies-derived antitumor macrolide, functions as a novel topoisomerase II poison
	Xie, Cheng-Ying; Zhu, Hong ; Lin, Li-Fling ; Miao, Ze-Hong ; Geng, Mei-Yu; Cai, Yu-Jun ; Chen, Yi; Zhao, Hua-Jun ; Luo, Hai-Bin ; Zhang, Xiong-Wen
刊名	MOLECULAR CANCER THERAPEUTICS
	2007-11
卷号	6 期号:11 页码:3059-3070
ISSN号	1535-7163
DOI	10.1158/1535-7163.MCT-07-0014
文献子类	Article
英文摘要	14-Ethyl-2,5,11-trimethyl-4,13,19,20-tetraoxa-tricyclo [14.2.1.1(7,10)]eicosane-3,12-dione (MFTZ-1), a new macrolide compound isolated from Streptomyces sp. ls9131, displayed wide cytotoxicity in human tumor cell lines with an average IC50 of 0.905 mu mol/L. Notably, MFTZ-1 showed significant cytotoxicity in the three multidrug resistance cell lines with an average resistance factor of 2.08. The in vivo experiments showed that MFTZ-1 had inhibitory effects on the human ovarian carcinoma HO-8910 cell line xenotransplanted in nude mice. Further studies showed that MFTZ-1 induced DNA double-strand breaks and triggered mitochondria-dependent apoptosis in human leukemia HL-60 cells. Using a yeast genetic system, we found that topoisomerase (Topo) II rather than Topo I was the primary cellular target of MFTZ-1. Most importantly, MFTZ-1 functions as a novel nonintercalative Topo II poison via binding to ATPase of Topo II, characterized by its strong inhibition on the decatenation and relaxation of Topo II. The capacity of MFTZ-1 to stabilize Topo II-DNA covalent complexes was comparable with that of the classic Topo II poison, etoposide. Moreover, using a Topo II catalytic inhibitor aclarubicin and Topo [I-deficient HL-60/MX2 cells, we further showed that MFTZ-1-triggered DNA doublestrand breaks and apoptosis occurred in a Topo II-dependent manner. Together, the well-defined Topo II-poisoning function and the potent antitumor activity, with the appreciable anti-multidrug resistance action in particular, promises MFTZ-1 as a novel potential Topo II-targeted agent, which merits further research and development. [Mol Cancer Ther 2007;6(11):3059 - 70].
WOS关键词	DRUG-INDUCED APOPTOSIS ; MEDIATED DNA CLEAVAGE ; DOUBLE-STRAND BREAK ; MULTIDRUG-RESISTANCE ; CELL-DEATH ; STREPTOMYCES-GLOBISPORUS ; P-GLYCOPROTEIN ; ETOPOSIDE ; DAMAGE ; COMPLEXES
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000251096600024
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273127]
专题	成果转移转化处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	Lin, Li-Fling
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 200031, Peoples R China 3.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources W China, Kunming, Peoples R China
推荐引用方式 GB/T 7714	Xie, Cheng-Ying,Zhu, Hong,Lin, Li-Fling,et al. MFTZ-1, an actinomycetes subspecies-derived antitumor macrolide, functions as a novel topoisomerase II poison[J]. MOLECULAR CANCER THERAPEUTICS,2007,6(11):3059-3070.
APA	Xie, Cheng-Ying.,Zhu, Hong.,Lin, Li-Fling.,Miao, Ze-Hong.,Geng, Mei-Yu.,...&Ding, Jian.(2007).MFTZ-1, an actinomycetes subspecies-derived antitumor macrolide, functions as a novel topoisomerase II poison.MOLECULAR CANCER THERAPEUTICS,6(11),3059-3070.
MLA	Xie, Cheng-Ying,et al."MFTZ-1, an actinomycetes subspecies-derived antitumor macrolide, functions as a novel topoisomerase II poison".MOLECULAR CANCER THERAPEUTICS 6.11(2007):3059-3070.