title: MFTZ-1, an actinomycetes subspecies derived antitumor macrolide, functions as a novel topoisomerase II poison.
abstract: 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. Is9131, displayed wide cytotoxicity in human tumor cell lines with an average IC(50) of 0.905 micromol/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 II-deficient HL-60/MX2 cells, we further showed that MFTZ-1-triggered DNA double-strand 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.
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Xie
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Lin
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Geng
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Cai
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Hua-Jun
authors.initials: HJ
authors.lastname: Zhao
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
authors.forename: Xiong-Wen
authors.initials: XW
authors.lastname: Zhang
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Fan
authors.forename: Yue-Mao
authors.initials: YM
authors.lastname: Shen
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D039903:Actinobacteria / Q000737:chemistry*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D015777:Eicosanoids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D018942:Macrolides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D059005:Topoisomerase II Inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: C526293:14-ethyl-2,5,11-trimethyl-4,13,19,20-tetraoxa-tricyclo(14.2.1.1(7,10))eicosane-3,12-dione; D000970:Antineoplastic Agents; D015777:Eicosanoids; D007364:Intercalating Agents; D018942:Macrolides; D059005:Topoisomerase II Inhibitors; D004247:DNA; D000251:Adenosine Triphosphatases; D004264:DNA Topoisomerases, Type I