NK314, a novel topoisomerase II inhibitor, induces rapid DNA double-strand breaks and exhibits superior antitumor effects against tumors resistant to other topoisomerase II inhibitors

Onda, Takeshi; Toyoda, Eiji; Miyazaki, Osamu; Seno, Chieko; Kagaya, Shigehide; Okamoto, Kazuya; Nishikawa, Kiyohiro

doi:10.1016/j.canlet.2007.10.004

Cited by 36 publications

(28 citation statements)

References 28 publications

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“…28,29 NK314, a synthetic derivative of benzo[c]phenanthridine, is a unique anticancer agent possessing specific and potent inhibitory activity against topoisomerase II␣ (Top2␣). [30][31][32] We found that NK314 inhibited ATL cell lines with greater potency than etoposide, a Top2 inhibitor frequently used in practice. Because the range of 50% inhibitory concentration values of NK314 for ATL cell lines and non-ATL cell lines differs from those of etoposide, we investigated other targets of NK314 for induction of apoptosis and inhibition of cell growth of ATL cell lines.…”

Section: Introductionmentioning

confidence: 89%

NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase

Hisatomi

Sueoka‐Aragane

Sato

et al. 2011

Blood

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Section: Introductionmentioning

confidence: 89%

NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase

Hisatomi

Sueoka‐Aragane

Sato

et al. 2011

Blood

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“…Specifically Induces Top2␣-DNA Complex-We previously showed that NK314 induced Top2 complexes and DSBs in several tumor cell lines (29,30). In this article, we first performed PFGE analysis of genomic DNA from drug-treated Nalm-6 cells (Fig.…”

Section: Nk314mentioning

confidence: 99%

“…NK314 is a novel synthetic benzo [c]phenanthridine alkaloid that exhibits strong antitumor activity (29). We previously reported that the drug stabilizes Top2 cleavage complexes and induces rapid DSBs to cause G 2 arrest in tumor cells (29,30).…”

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confidence: 99%

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NK314, a Topoisomerase II Inhibitor That Specifically Targets the α Isoform

Toyoda

Kagaya

Cowell

et al. 2008

Journal of Biological Chemistry

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108

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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 Top2␤ 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 Top2␤ 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 TOP2␤ homozygous knock-out cells display increased NK314 sensitivity, indicating that the ␣ isoform is the cellular target. We further show that the absence of Top2␤ 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. DNA topoisomerase II (Top2)2 is a ubiquitous nuclear enzyme that alters the topological structure of DNA and chromosomes through a transient DNA double-strand break (DSB) and subsequent religation of the DSB (1, 2). The enzyme has been implicated in many aspects of DNA metabolism, including DNA replication, repair, transcription, and chromosome condensation/segregation (1, 3). Top2 has been of considerable interest to human medicine, because it is an important target for cancer chemotherapy (4). Top2-targeting agents, involving etoposide, doxorubicin, and mitoxantrone, are among the most effective and widely used anticancer drugs in cancer chemotherapy (5, 6). These agents are referred to as "Top2 poisons," because they convert the essential enzyme into a highly cytotoxic DNA-damaging agent through the formation of "cleavage complex" (also called "cleavable complex"), in which a Top2-linked DNA strand-passing intermediate is stabilized, allowing the generation of a DSB (7,8).Mammalian cells possess two genetically distinct Top2 isoforms (9, 10). Despite their similar structural features (ϳ70% identity at the amino acid level) and biological properties, the two isoforms are differentially regulated and play different roles in living cells. Top2␣ is most abundantly expressed in rapidly growing tissues and its expression is cell cycle-regulated...

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“…They were inhibited by the antioxidants like NAC, suggesting that their formation was mediated by ROS. Cellular processing converts these complexes into permanent DNA strand breaks that trigger cell death (Binaschi et al, 1995;Champoux, 2001;Onda et al, 2008;Sordet et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Carboplatin resistant human laryngeal carcinoma cells are cross resistant to curcumin due to reduced curcumin accumulation

Rak

Čimbora‐Zovko

Gajski

et al. 2013

Toxicology in Vitro

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NK314, a novel topoisomerase II inhibitor, induces rapid DNA double-strand breaks and exhibits superior antitumor effects against tumors resistant to other topoisomerase II inhibitors

Cited by 36 publications

References 28 publications

NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase

NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase

NK314, a Topoisomerase II Inhibitor That Specifically Targets the α Isoform

Carboplatin resistant human laryngeal carcinoma cells are cross resistant to curcumin due to reduced curcumin accumulation

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