Maleimide Is a Potent Inhibitor of Topoisomerase II in Vitro and in Vivo: A New Mode of Catalytic Inhibition

Jensen, Lars H.; Renodon-Cornière, Axelle; Wessel, Irene; Langer, Seppo W.; Søkilde, Birgitte; Carstensen, Elisabeth V.; Sehested, Maxwell; Jensen, Peter Buhl

doi:10.1124/mol.61.5.1235

Cited by 48 publications

(44 citation statements)

References 24 publications

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“…Suramin inhibits binding of topoisomerase II to DNA but also inhibits the binding of certain growth factors to their receptors (49). Maleimide is thought to covalently modify topoisomerase II cysteine residues, thereby reducing the amount of catalytically active enzyme, but could also modify multiple cysteine-containing proteins (50). The similar results obtained with the three independent inhibitors provide good support for the view that the early apoptosis induced by adduct-forming treatments is independent of topoisomerase II-mediated effects.…”

Section: Discussionsupporting

confidence: 75%

Doxorubicin-DNA Adducts Induce a Non-Topoisomerase II–Mediated Form of Cell Death

Swift

Rephaeli²,

Nudelman³

et al. 2006

Cancer Research

270

203

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Doxorubicin (Adriamycin) is one of the most commonly used chemotherapeutic drugs and exhibits a wide spectrum of activity against solid tumors, lymphomas, and leukemias. Doxorubicin is classified as a topoisomerase II poison, although other mechanisms of action have been characterized. Here, we show that doxorubicin-DNA adducts ( formed by the coadministration of doxorubicin with non-toxic doses of formaldehyde-releasing prodrugs) induce a more cytotoxic response in HL-60 cells than doxorubicin as a single agent. Doxorubicin-DNA adducts seem to be independent of classic topoisomerase II-mediated cellular responses (as observed by employing topoisomerase II catalytic inhibitors and HL-60/ MX2 cells). Apoptosis induced by doxorubicin-DNA adducts initiates a caspase cascade that can be blocked by overexpressed Bcl-2, suggesting that adducts induce a classic mode of apoptosis. A reduction in the level of topoisomerase IImediated double-strand-breaks was also observed with increasing levels of doxorubicin-DNA adducts and increased levels of apoptosis, further confirming that adducts exhibit a separate mechanism of action compared with the classic topoisomerase II poison mode of cell death by doxorubicin alone. Collectively, these results indicate that the presence of formaldehyde transfers doxorubicin from topoisomerase IImediated cellular damage to the formation of doxorubicin-DNA adducts, and that these adducts are more cytotoxic than topoisomerase II-mediated lesions. These results also show that doxorubicin can induce apoptosis by a non-topoisomerase II-dependent mechanism, and this provides exciting new prospects for enhancing the clinical use of this agent and for the development of new derivatives and new tumor-targeted therapies. (Cancer Res 2006; 66(9): 4863-71)

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Section: Discussionsupporting

confidence: 75%

Doxorubicin-DNA Adducts Induce a Non-Topoisomerase II–Mediated Form of Cell Death

Swift

Rephaeli²,

Nudelman³

et al. 2006

Cancer Research

270

203

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“…To establish a dose-response relationship, we next carried out decatenation of Crithidia fasciculata kDNA as described previously (ref. 21; Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…Topoisomerase II catalytic activity (DNA strand passage activity) was measured using a filter-based kinetoplast DNA (kDNA) decatenation assay as described (21 Primers used in the PCR reaction were forward 5V -GAAATACGAGA-CTGCTCGGC-3V and reverse 5V -TTAAAACTCATAGTCTTCATCAG-3V . The DNA fragment was isolated from unincorporated deoxynucleotide triphosphates by ethanol precipitation at 0.3 mol/L NaCl followed by washing in 70% ethanol.…”

Section: Methodsmentioning

confidence: 99%

“…To identify novel structural entities targeting topoisomerase II as catalytic inhibitors, we have screened 1,990 compounds from the National Cancer Institute (NCI) diversity set library against human topoisomerase IIa by using a filter-based decatenation assay (21). Here, we characterize the biological activity of NSC35866, a S 6 -substituted thioguanine analogue identified in this screen.…”

Section: Introductionmentioning

confidence: 99%

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Substituted Purine Analogues Define a Novel Structural Class of Catalytic Topoisomerase II Inhibitors

et al. 2005

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By screening 1,990 compounds from the National Cancer Institute diversity set library against human topoisomerase IIA, we identified a novel catalytic topoisomerase II inhibitor NSC35866, a S 6 -substituted analogue of thioguanine. In addition to inhibiting the DNA strand passage reaction of human topoisomerase IIA, NSC35866 also inhibited its ATPase reaction. NSC35866 primarily inhibited DNA-stimulated ATPase activity, whereas DNA-independent ATPase activity was less sensitive to inhibition. We compared the mode of topoisomerase II ATPase inhibition induced by NSC35866 with that of 12 other substituted purine analogues of different chemical classes. The ability of thiopurines with free SH functionalities to inhibit topoisomerase II ATPase activity was completely abolished by DTT, suggesting that these thiopurines inhibit topoisomerase II ATPase activity by covalently modifying free cysteine residues. In contrast, NSC35866 as well as two O 6 -substituted guanine analogues, O 6 -benzylguanine and NU2058, could inhibit topoisomerase II ATPase activity in the presence of DTT, indicating that they have a different mechanism of inhibition. NSC35866 did not increase the level of topoisomerase II covalent cleavable complexes with DNA, indicating that it is a catalytic inhibitor and not a poison. NSC35866 was also capable of inducing a salt-stable complex of topoisomerase II on closed circular DNA. In accordance with these biochemical data, NSC35866 could antagonize etoposide-induced cytotoxicity and DNA breaks in human and murine cancer cells, confirming that NSC35866 also functions as a catalytic topoisomerase II inhibitor in cells. (Cancer Res 2005; 65(16): 7470-7)

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“…Using biochemical analyses, we and other researchers demonstrated that the catalytic activity of Topo IIα was sensitive to "Michael acceptors" due to the existence of nucleophilic thiol (-SH) residues in the active center. [4][5][6] Because xanthocidin derivatives (#1 and #2) contain an exo-methylene ketone group (a possible reactive electrophilic moiety, see Fig. 1), whether they behaved as an inhibitor of Topo IIα through this group was investigated in the present study.…”

mentioning

confidence: 99%

Xanthocidin Derivatives as Topoisomerase IIα Enzymatic Inhibitors

Takeda

Yaji

Matsumoto

et al. 2014

Biological & Pharmaceutical Bulletin

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Few studies have examined xanthocidin, a biotic isolated from Streptomyces xanthocidicus in 1966, because its supply is limited. Based on its chemical structure, xanthocidin has the potential to become a lead compound in the production of agrochemicals and anti-cancer drugs; however, it is unstable under both basic and acidic conditions. We recently established the total synthesis of xanthocidin using the FeCl 3 -mediated Nazarov reaction, and obtained two stable derivatives (#1 and #2). The results of the present study demonstrated that these derivatives exhibited the inhibitory activity of topoisomerase IIα, known as a molecular target for cancer chemotherapy, and this was attributed to the respective exo-methylene ketone group without DNA intercalation. The results obtained also suggest that these derivatives may have value as lead compounds in the synthesis of topoisomerase IIα inhibitors. 1) Xanthocidin has a highly oxidized five-membered ring with contiguous cis-vicinal diol (-OH), carboxylic acid (-COOH), and conjugated exo-methylene group substituents ( Fig. 1, upper panel). Key words1,2) Xanthocidin may be promising as a lead compound for the production of agrochemicals and anticancer drugs; however, it was shown to be unstable under both basic and acidic conditions.2) In addition, few studies have assessed its bioactivity due to its limited supply.3) We successfully established the total synthesis of xanthocidin using the FeCl 3 -mediated Nazarov reaction, 2) and obtained two stable xanthocidin derivatives (#1 and #2) (Fig. 1, upper panel) that exhibited anti-proliferative effects on highly aggressive human breast cancer MDA-MB-231 cells. 4) Although the biological activities of these derivatives imply their possible use as antiproliferative agents for cancer cells, their action point(s) have not yet been resolved.Catalytic inhibitors of topoisomerase IIα (Topo IIα), without DNA intercalating potential, were previously shown to be useful in targeting tumors that expressed markedly higher levels of Topo IIα (i.e., MDA-MB-231 cells) than those of normal cells. Using biochemical analyses, we and other researchers demonstrated that the catalytic activity of Topo IIα was sensitive to "Michael acceptors" due to the existence of nucleophilic thiol (-SH) residues in the active center.4-6) Because xanthocidin derivatives (#1 and #2) contain an exo-methylene ketone group (a possible reactive electrophilic moiety, see Fig. 1), whether they behaved as an inhibitor of Topo IIα through this group was investigated in the present study. We also analyzed their DNA intercalation potential. The results obtained indicated that the xanthocidin derivatives have inhibitory activity of Topo IIα as catalytic inhibitors of the enzyme, and that they did not have DNA intercalating potential. MATERIALS AND METHODSReagents Xanthocidin derivatives (#1 and #2) were synthesized according to our previously established methods. 2)These synthesized compounds were purified by HPLC or column chromatography, and their purity (>98%) was con...

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Maleimide Is a Potent Inhibitor of Topoisomerase II in Vitro and in Vivo: A New Mode of Catalytic Inhibition

Cited by 48 publications

References 24 publications

Doxorubicin-DNA Adducts Induce a Non-Topoisomerase II–Mediated Form of Cell Death

Doxorubicin-DNA Adducts Induce a Non-Topoisomerase II–Mediated Form of Cell Death

Substituted Purine Analogues Define a Novel Structural Class of Catalytic Topoisomerase II Inhibitors

Xanthocidin Derivatives as Topoisomerase IIα Enzymatic Inhibitors

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