5-(N-phenylcarboxamido)-2-thiobarbituric acid (NSC 336628), a novel potential antitumor agent

Brewer, A. D.; Minatelli, John A.; Plowman, Jacqueline; Paull, Kenneth D.; Narayanan, V. L.

doi:10.1016/0006-2952(85)90335-1

Cited by 37 publications

(13 citation statements)

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“…(Fig. 1) is a catalytic inhibitor of topoisomerase II (18,27,28) that displays curative activity against some murine cancer models (26,50) and is currently in human clinical trials (29 -32). The effects of this drug on the activity of human topoisomerase II␣ (which represents the major topoisomerase II isoform present in rapidly proliferating human cells) as well as the type II enzymes from Drosophila and yeast are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

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Merbarone Inhibits the Catalytic Activity of Human Topoisomerase IIα by Blocking DNA Cleavage

Fortune¹,

Osheroff²

1998

Journal of Biological Chemistry

254

241

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Merbarone is a catalytic inhibitor of topoisomerase II that is in clinical trials as an anticancer agent. Despite the potential therapeutic value of this drug, the mechanism by which it blocks topoisomerase II activity has not been delineated. Therefore, to determine the mechanistic basis for the inhibitory action of merbarone, the effects of this drug on individual steps of the catalytic cycle of human topoisomerase II␣ were assessed. Concentrations of merbarone that inhibited catalytic activity >80% had no effect on either enzyme⅐DNA binding or ATP hydrolysis. In contrast, the drug was a potent inhibitor of enzyme-mediated DNA scission (in the absence or presence of ATP), and the inhibitory profiles of merbarone for DNA cleavage and relaxation were similar. These data indicate that merbarone acts primarily by blocking topoisomerase II-mediated DNA cleavage. Merbarone inhibited DNA scission in a global (rather than site-specific) fashion but did not appear to intercalate into DNA or bind in the minor groove. Since the drug competed with etoposide (a cleavage-enhancing agent that binds directly to topoisomerase II), it is proposed that merbarone exerts its inhibitory effects through interactions with the enzyme and that the drug shares an interaction domain on topoisomerase II with cleavage-enhancing agents.Topoisomerase II is the target for some of the most active anticancer drugs used in the treatment of human malignancies (1-6). Among the topoisomerase II-targeted agents currently in clinical use are etoposide, teniposide, doxorubicin, mitoxantrone, and amsacrine. These drugs kill cells in an unusual fashion. Rather than inhibiting the overall catalytic activity of the type II enzyme, they act by increasing levels of topoisomerase II-mediated DNA cleavage, thus converting this essential enzyme into a potent cellular toxin (1, 3, 5, 7-10). Hence, to distinguish their unique mechanism of action, they are referred to as topoisomerase II "poisons" (11).A second class of drugs that affect the activity of topoisomerase II also appears to have clinical potential (2, 5, 7). In contrast to poisons, these agents act by inhibiting the catalytic activity of the enzyme and display no ability to stimulate DNA cleavage. Originally, topoisomerase II "catalytic inhibitors" were defined by antibacterial compounds such as novobiocin and coumermycin (12). These coumarin-based drugs block the DNA strand passage activity of the prokaryotic type II enzyme, DNA gyrase, by interfering with the ability of the enzyme to bind its ATP cofactor (13-17).Recently, catalytic inhibitors that display high activity against eukaryotic type II topoisomerases have been described. These are typified by drugs such as merbarone (18), aclarubicin (20), fostriecin (21), staurosporine (22), and mitindomide (23), which reflect a variety of inhibitory mechanisms. Aclarubicin, for example, blocks binding of the enzyme to its DNA substrate, the initial step of the topoisomerase II catalytic cycle (24) (see Fig. 12). In contrast, ICRF-193 blocks the final s...

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Section: Methodsmentioning

confidence: 99%

“…However, the fact that the IC 50 for merbarone inhibition of DNA cleavage is unaffected by ATP implies that this drug does not interfere with ATP utilization. To address this issue directly, the effects of merbarone on the ATPase activity of human topoisomerase II␣ were determined (Fig.…”

Section: Inhibition Of Topoisomerase II Catalytic Activity By Merbaromentioning

confidence: 99%

Merbarone Inhibits the Catalytic Activity of Human Topoisomerase IIα by Blocking DNA Cleavage

Fortune¹,

Osheroff²

1998

Journal of Biological Chemistry

254

241

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“…1 Beside the effects as CNS depressants, barbiturates have been shown to exhibit wide variety of other biological activities, including anti-tumor activities, immuno-modulating activities, herbicidal or insecticidal activities, PPARγ agonistic activities, and inhibitory activities against mucosal addressin cell adhesion molecule-1 interactions. [2][3][4][5][6] Notably, barbiturates, including phenobarbital and secobarbital, were also found to inhibit the phosphatase activity of calcineurin, a protein Ser/Thr phosphatase. 7 In view of this observation, we considered the barbituric acid moiety as a candidate scaffold for the design of protein tyrosine phosphatase (PTP) inhibitors.…”

Section: -70mentioning

confidence: 99%

Barbituric Acid Derivatives as Protein Tyrosine Phosphatase Inhibitors

Kafle

Bhattarai²,

Cho³

2011

Bulletin of the Korean Chemical Society

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“…Etoposide acts by stabilizing the reaction intermediate generated by double strand cleavage by topoisomerase II, preventing strand religation and resulting in increased double strand breaks. Merbarone is an alternative topoisomerase II inhibitor that acts by inhibiting the initial double strand cleavage by topoisomerase II (Brewer et al, 1985;Cooney et al, 1985;Glover et al, 1987). Both agents inhibit cell cycle progression and DNA replication, and both are similarly cytotoxic.…”

Section: Sine Activation By Topoisomerase Inhibitors Correlates With mentioning

confidence: 99%

DNA cleavage and Trp53 differentially affect SINE transcription

Hagan

Rudin

2006

Genes Chromosomes & Cancer

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Among the cellular responses observed following treatment with DNA-damaging agents is the activation of Short Interspersed Elements (SINEs; retrotransposable genetic elements that comprise over 10% of the human genome). By placing a human SINE (the Alu element) into murine cells, we have previously shown that DNA-damaging agents such as etoposide can induce both upregulation of SINE transcript levels and SINE retrotransposition. A similarly cytotoxic (but not genotoxic) exposure to vincristine was not associated with SINE activation. Here we demonstrate that multiple other genotoxic exposures are associated with upregulation of SINE transcript levels. By comparing the effects of similarly cytotoxic doses of the topoisomerase II inhibitors etoposide and merbarone, we confirm that DNA strand breakage is specifically associated with SINE induction. By evaluating transcription rate and RNA stability, we demonstrate that SINE induction by genotoxic exposure is associated with transcriptional induction and not with transcript stabilization. Finally we demonstrate that SINE induction by genotoxic stress is mediated by a Trp53-independent pathway, and in fact that Trp53 plays an inhibitory role in attenuating the transcriptional induction of SINE elements following exposure to a genotoxic agent. Together these data support a model in which initial DNA damage can trigger genomic instability due to SINE activation, a response which may be amplified in cancer cells lacking functional TP53.

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5-(N-phenylcarboxamido)-2-thiobarbituric acid (NSC 336628), a novel potential antitumor agent

Cited by 37 publications

References 0 publications

Merbarone Inhibits the Catalytic Activity of Human Topoisomerase IIα by Blocking DNA Cleavage

Merbarone Inhibits the Catalytic Activity of Human Topoisomerase IIα by Blocking DNA Cleavage

Barbituric Acid Derivatives as Protein Tyrosine Phosphatase Inhibitors

DNA cleavage and Trp53 differentially affect SINE transcription

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