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 ; Fan, Li-Ming ; Shen, Yue-Mao ; Ding, Jian
	2007-11-01
发表期刊	MOLECULAR CANCER THERAPEUTICS
卷号	6 期号:11 页码:3059-3070
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].
DOI	10.1158/1535-7163.MCT-07-0014
收录类别	SCI
语种	英语
WOS记录号	WOS:000251096600024
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/23849
专题	植物化学与西部植物资源持续利用国家重点实验室
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.

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