NK314 - CAS 208237-49-4
Catalog number:
208237-49-4
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
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Description:
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.
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Purity:
0.98
Appearance:
Solid powder
Synonyms:
NK314; NK-314; NK 314.
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1.NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase II{alpha} and DNA-dependent protein kinase.
Hisatomi T1, Sueoka-Aragane N, Sato A, Tomimasu R, Ide M, Kurimasa A, Okamoto K, Kimura S, Sueoka E. Blood. 2011 Mar 31;117(13):3575-84. doi: 10.1182/blood-2010-02-270439. Epub 2011 Jan 18.
Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease, incurable by standard chemotherapy. NK314, a new anticancer agent possessing inhibitory activity specific for topoisomerase IIα (Top2α), inhibited the growth of various ATL cell lines (50% inhibitory concentration: 23-70nM) with more potent activity than that of etoposide. In addition to the induction of DNA double-strand breaks by inhibition of Top2α, NK314 induced degradation of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), resulting in impaired DNA double-strand break repair. The contribution of DNA-PK to inhibition of cell growth was affirmed by the following results: NK314 inhibited cell growth of M059J (a DNA-PKcs-deficient cell line) and M059K (a cell line with DNA-PKcs present) with the same potency, whereas etoposide exhibited weak inhibition of cell growth with M059K cells. A DNA-PK specific inhibitor, NU7026, enhanced inhibitory activity of etoposide on M059K as well as on ATL cells.
2.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 T1, Toyoda E, Miyazaki O, Seno C, Kagaya S, Okamoto K, Nishikawa K. Cancer Lett. 2008 Jan 18;259(1):99-110. Epub 2007 Nov 12.
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.
3.DNA-dependent protein kinase and ataxia telangiectasia mutated (ATM) promote cell survival in response to NK314, a topoisomerase IIα inhibitor.
Guo L1, Liu X, Jiang Y, Nishikawa K, Plunkett W. Mol Pharmacol. 2011 Aug;80(2):321-7. doi: 10.1124/mol.109.057125. Epub 2011 May 5.
4-Hydroxy-5-methoxy-2,3-dihydro-1H-[1,3]benzodioxolo[5,6-c]pyrrolo[1,2-f]-phenanthridium chloride (NK314) is a benzo[c] phenanthridine alkaloid that inhibits topoisomerase IIα, leading to the generation of DNA double-strand breaks (DSBs) and activating the G(2) checkpoint pathway. The purpose of the present studies was to investigate the DNA intercalating properties of NK314, to evaluate the DNA repair mechanisms activated in cells that may lead to resistance to NK314, and to develop mechanism-based combination strategies to maximize the antitumor effect of the compound. A DNA unwinding assay indicated that NK314 intercalates in DNA, a property that likely cooperates with its ability to trap topoisomerase IIα in its cleavage complex form. The consequence of this is the formation of DNA DSBs, as demonstrated by pulsed-field gel electrophoresis and H2AX phosphorylation. Clonogenic assays demonstrated a significant sensitization in NK314-treated cells deficient in DNA-dependent protein kinase (DNA-PK) catalytic subunit, Ku80, ataxia telangiectasia mutated (ATM), BRCA2, or XRCC3 compared with wild-type cells, indicating that both nonhomologous end-joining and homologous recombination DNA repair pathways contribute to cell survival.
4.Inhibition of topoisomerase IIalpha and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials.
Guo L1, Liu X, Nishikawa K, Plunkett W. Mol Cancer Ther. 2007 May;6(5):1501-8.
NK314 is a novel synthetic benzo[c]phenanthridine alkaloid that has recently entered clinical trials as an antitumor compound, based on impressive activities in preclinical models. The present investigations were directed at determining the mechanism of action of this agent. NK314 induced significant G(2) cell cycle arrest in several cell lines, independent of p53 status, suggesting the existence of a common mechanism of checkpoint activation. The Chk1-Cdc25C-Cdk1 G(2) checkpoint pathway was activated in response to 100 nmol/L NK314 in ML-1 human acute myeloid leukemia cells. This was associated with the phosphorylation of the histone variant H2AX, an action that was predominant in the G(2) population, suggesting that double-strand DNA breaks caused cells to activate the checkpoint pathway. Double-strand DNA breaks were visualized as chromosomal aberrations when the G(2) checkpoint was abrogated by 7-hydroxystaurosporine. In vitro assays showed that NK314 inhibited the ability of topoisomerase IIalpha to relax supercoiled DNA and trapped topoisomerase IIalpha in its cleavage complex intermediate.
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CAS 208237-49-4 NK314

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