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• W2151837692 abstract "Abstract 14-Ethyl-2,5,11-trimethyl-4,13,19,20-tetraoxa-tricyclo[14.2.1.17,10]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 IC50 of 0.905 μmol/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. [Mol Cancer Ther 2007;6(11):3059–70]" @default.
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• W2151837692 date "2007-11-01" @default.
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• W2151837692 title "MFTZ-1, an actinomycetes subspecies–derived antitumor macrolide, functions as a novel topoisomerase II poison" @default.
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• W2151837692 doi "https://doi.org/10.1158/1535-7163.mct-07-0014" @default.
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