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.
NK314 is a novel synthetic benzo[c]phenanthridine alkaloid that shows strong antitumor activity. It inhibited topoisomerase II activity and stabilized topoisomerase II-DNA cleavable complexes. The DNA breaks occurred within 1h after treatment with NK314 even without digestion of topoisomerase II by proteinase K, whereas etoposide required digestion of the enzyme protein in cleavable complex to detect DNA breaks. Pretreatment with topoisomerase II catalytic inhibitors, ICRF-193 and suramin, reduced both cleavable complex-mediated DNA breaks and proteinase K-independent DNA breaks, but protease inhibitors and nuclease inhibitors only decreased the latter. These results indicate that NK314 might affect topoisomerase II in the different manner from cleavable complex formation and activate intracellular proteinase and nuclease to produce DNA fragmentation. As a result of this unique mechanism of DNA breakage, NK314 showed substantial growth inhibition of topoisomerase II inhibitor-resistant tumors.
Onda
Takeshi
T
Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo 115-8588, Japan. takeshi.onda@nipponkayaku.co.jp <takeshi.onda@nipponkayaku.co.jp>
Toyoda
Eriko
E
Miyazaki
Osamu
O
Seno
Chieko
C
Kagaya
Shigehide
S
Okamoto
Kazuya
K
Nishikawa
Kiyohiro
K
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D019286:Endopeptidase K / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007941:Leukemia P388; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D059005:Topoisomerase II Inhibitors; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C522060:NK314; D010616:Phenanthrenes; D059005:Topoisomerase II Inhibitors; D019286:Endopeptidase K; D004250:DNA Topoisomerases, Type II