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: Cheng-Ying Xie, Hong Zhu, Li-Ping Lin, Ze-Hong Miao, Mei-Yu Geng, Yu-Jun Cai, Yi Chen, Hua-Jun Zhao, Hai-Bin Luo, Xiong-Wen Zhang, Li-Ming Fan, Yue-Mao Shen, Jian Ding
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 11 Pg. 3059-70 (Nov 2007) ISSN: 1535-7163 [Print] United States
• PMID: 18025289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 14-ethyl-2,5,11-trimethyl-4,13,19,20-tetraoxa-tricyclo(14.2.1.1(7,10))eicosane-3,12-dione
• Antineoplastic Agents
• Eicosanoids
• Intercalating Agents
• Macrolides
• Topoisomerase II Inhibitors
• DNA
• Adenosine Triphosphatases
• DNA Topoisomerases, Type I

Topics

• Actinobacteria (chemistry)
• Adenosine Triphosphatases (metabolism)
• Animals
• Antineoplastic Agents (chemistry, isolation & purification, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA (metabolism)
• DNA Breaks, Double-Stranded (drug effects)
• DNA Topoisomerases, Type I (metabolism)
• Eicosanoids (chemistry, isolation & purification, pharmacology)
• Female
• Humans
• Intercalating Agents (pharmacology)
• Macrolides (chemistry, isolation & purification, pharmacology)
• Mice
• Mitochondria (drug effects)
• Saccharomyces cerevisiae (cytology, drug effects, enzymology)
• Topoisomerase II Inhibitors
• Xenograft Model Antitumor Assays