This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Xie, C.-Y. Articles by Ding, J. Search for Related Content PubMed PubMed Citation Articles by Xie, C.-Y. Articles by Ding, J.

Research Articles: Therapeutics, Targets, and Development

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

¹ Division of Antitumor Pharmacology, and ² Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China; and ³ The State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, P.R. China

Requests for reprints: Jian Ding, Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-tech Park, Shanghai 201203, P.R. China. Phone: 86-21-50806079; Fax: 86-21-50806722. E-mail: jding{at}mail.shcnc.ac.cn or Li-Ping Lin, Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, P.R. China. Phone: 86-21-50806600, ext. 2423; Fax: 86-21-50806722. E-mail: lplin{at}jding.dhs.org

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 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]

Grant support: National Natural Science Foundation of China grant 30572201.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/ 8/07; revised 9/ 7/07; accepted 9/25/07.