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J. Biol. Chem., Vol. 283, Issue 35, 23711-23720, August 29, 2008

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NK314, a Topoisomerase II Inhibitor That Specifically Targets the Isoform^*

Eriko Toyoda, Shigehide Kagaya, Ian G. Cowell^¶, Aya Kurosawa, Keiichi Kamoshita, Kiyohiro Nishikawa, Susumu Iiizumi, Hideki Koyama, Caroline A. Austin^¶, and Noritaka Adachi¹

From the International Graduate School of Arts and Sciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan, the Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., 31-12, Shimo 3-chome, Kita-ku, Tokyo 115-8588, Japan, and the ^¶Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Newcastle-upon-Tyne, NE2 4HH United Kingdom

Topoisomerase II (Top2) is a ubiquitous nuclear enzyme that relieves torsional stress in chromosomal DNA during various cellular processes. Agents that target Top2, involving etoposide, doxorubicin, and mitoxantrone, are among the most effective anticancer drugs used in the clinic. Mammalian cells possess two genetically distinct Top2 isoforms, both of which are the target of these agents. Top2 is essential for cell proliferation and is highly expressed in vigorously growing cells, whereas Top2β is nonessential for growth and has recently been implicated in treatment-associated secondary malignancies, highlighting the validity of a Top2-specific drug for future cancer treatment; however, no such agent has been hitherto reported. Here we show that NK314, a novel synthetic benzo[c]phenanthridine alkaloid, targets Top2 and not Top2β in vivo. Unlike other Top2 inhibitors, NK314 induces Top2-DNA complexes and double-strand breaks (DSBs) in an isoform-specific manner. Heterozygous disruption of the human TOP2 gene confers increased NK314 resistance, whereas TOP2β homozygous knock-out cells display increased NK314 sensitivity, indicating that the isoform is the cellular target. We further show that the absence of Top2β does not alleviate NK314 hypersensitivity of cells deficient in non-homologous end-joining, a critical pathway for repairing Top2-mediated DSBs. Our results indicate that NK314 acts as a Top2-specific poison in mammalian cells, with excellent potential as an efficacious and safe chemotherapeutic agent. We also suggest that a series of human knock-out cell lines are useful in assessing DNA damage and repair induced by potential topoisomerase-targeting agents.

Received for publication, May 22, 2008 , and in revised form, June 27, 2008.

^* This work was supported in part by Yokohama City University Strategic Research Project Grants W18006 [GenBank] and K19009 (to N. A.), and by Grant-in-Aids from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan Project numbers 18590063, 18058019, and 18018034 (to N. A.). 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.

¹ To whom correspondence should be addressed: International Graduate School of Arts and Sciences, Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan. Fax: 81-45-787-2228; E-mail: nadachi{at}yokohama-cu.ac.jp.

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