Mode of action of topoisomerase II-targeting agents at a specific DNA sequence

Sørensen, Boe Sandahl; Sinding, J.; Andersen, Anders H.; Alsner, Jan; Jensen, Peter Buhl; Westergaard, Ole

doi:10.1016/0022-2836(92)90863-f

Cited by 112 publications

(62 citation statements)

References 30 publications

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“…For example, Sorensen et al (36) have shown that the anthracycline aclarubicin inhibits the DNA cleavage activity of topoisomerase II by preventing the initial noncovalent DNA-binding reaction of the enzyme. The experimental evidence presented in the current study strongly suggests that the bis-benzimidazoles also act at an early stage in the processive reactions of topoisomerases I and II, before the initial strand cleavage can occur.…”

Section: Resultsmentioning

confidence: 99%

Selective inhibition of topoisomerases from Pneumocystis carinii compared with that of topoisomerases from mammalian cells

Dykstra

McClernon

Elwell

et al. 1994

Antimicrob Agents Chemother

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Type I and II topoisomerase activities were partially purified from Pneumocystis carinii. The catalytic (strand-passing) activities of both enzymes were selectively inhibited by members of a series of dicationicsubstituted bis-benzimidazoles compared with those of topoisomerases of mammalian (calf thymus) origin.The most active inhibitors of the parasite enzymes were also highly effective in an in vivo animal model of P.carinii pneumonia. Selected dicationic-substituted bis-benzimidazoles also strongly inhibited the induction of the topoisomerase I-and 11-mediated cleavable complex, suggesting that the biologically active DNA minor groove-binding molecules inhibit the enzyme-DNA binding step of the topoisomerase reaction sequence. The apparent selectivities for the parasite enzymes and the low levels of toxicity to mammalian cells for the biologically active bis-benzimidazoles suggest that these compounds hold promise as effective therapeutic agents in the treatment of a life-threatening AIDS-related disease, P. carinii pneumonia.Dicationic-substituted aromatic molecules related to pentamidine have long been known to be effective antiparasitic agents (35). Recent studies have found that a number of direct analogs of pentamidine have activity against Pneumocystis carinii (19), Giardia lamblia (3), Toxoplasma gondii (25), Cryptosporidium parvum (7), Leishmania amazonensis subsp. mexicana (5), and Plasmodium falciparum (5). A strong correlation was observed between compound activity against G. lamblia in vitro and DNA-binding ability (3). On the basis of those initial results, studies of antiparasitic compounds were extended to a series of compounds with much stronger DNA-binding affinities, the dicationic bis-benzimidazoles. As observed with the pentamidine analogs, a strong correlation was found between DNA binding strength and antigiardial activity for the bisbenzimidazole series [r2 = 0.96 versus calf thymus DNA and i2 = 0.97 versus poly(dA) * (dT)](4). Other studies confirmed that the effective antigiardial compounds were strong DNA minor groove-binding agents with an AT base pair preference (14). Molecular modeling calculations in that study showed that the DNA-binding strength for this class of compound depended on the radius of curvature on the basis of four defined moieties within the molecules, the distance between cationic moieties, the electronic effects from cationic substituents, and hydrogen bonding. There was no evidence of either an intercalative or a covalent interaction of these compounds with nucleic acids. The antigiardiasis study also revealed a convincing correlation between antitopoisomerase II activity and in vitro activity against G. lamblia for the dicationic bis-benzimidazoles (r2 = 0.91) (4). It is unclear whether these compounds manifest their antiparasitic activity primarily by binding to DNA, topoisomerase, or the enzyme-DNA binary complex.As part of a continuing investigation to determine the mechanism of the anti-P. carinii action of these dicationic molecules and to develop new ag...

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Section: Resultsmentioning

confidence: 99%

Selective inhibition of topoisomerases from Pneumocystis carinii compared with that of topoisomerases from mammalian cells

Dykstra

McClernon

Elwell

et al. 1994

Antimicrob Agents Chemother

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“…Drugs that inhibit topoisomerase II catalytic function act at different steps of the catalytic cycle. Aclarubicin is an anthracycline that blocks enzyme⅐DNA binding, the initial step of the cycle (24). Staurosporine, a tyrosine kinase inhibitor that also acts on topoisomerase II, inhibits DNA cleavage and ATP interactions (22).…”

Section: Discussionmentioning

confidence: 99%

“…Depending upon which step(s) of the topoisomerase II catalytic cycle is targeted by a specific agent, the cellular effects of that drug could be significantly different. For example, a compound such as aclarubicin, which disrupts topoisomerase II⅐DNA binding (24), would undermine both the catalytic and structural roles of the enzyme. In contrast, drugs such as merbarone, which act by blocking DNA cleavage, or coumarins, which act by blocking enzyme-ATP interactions (40,52), would only impact the catalytic functions of topoisomerase II.…”

Section: Discussionmentioning

confidence: 99%

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

Fortune¹,

Osheroff²

1998

Journal of Biological Chemistry

256

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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“…Topoisomerase II is a nuclear matrix-associated enzyme responsible for the cleavage and religation of dsDNA, a prerequisite for the structural reorganization of nuclear chromatin, and thus plays an essential role in the structural remodeling of nucleosomal chromatin (60,61). We therefore examined whether the activity of csp might involve chromatin remodeling and, if so, could be affected by novobiocin.…”

Section: P Gingivalis Facilitates Hiv-1 Reactivation Via Chromatin Rmentioning

confidence: 99%

Reactivation of Latent HIV-1 Infection by the Periodontopathic Bacterium Porphyromonas gingivalis Involves Histone Modification

Imai

Ochiai

Okamoto

2009

The Journal of Immunology

121

139

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Latently infected cells harbor the HIV-1 proviral DNA genome primarily integrated into heterochromatin, allowing the persistence of transcriptionally silent proviruses. Hypoacetylation of histone proteins by histone deacetylases (HDAC) is involved in the maintenance of HIV-1 latency by repressing viral transcription. In addition, periodontal diseases, caused by polymicrobial subgingival bacteria including Porphyromonas gingivalis, are among the most prevalent infections of mankind. Here we demonstrate the effects of P. gingivalis on HIV-1 replication. This activity could be ascribable to the bacterial culture supernatant but not to other bacterial components such as fimbriae or LPS. We found that this HIV-1-inducing activity was recovered in the lower molecular mass (<3 kDa) fraction of the culture supernatant. We also demonstrated that P. gingivalis produces high concentrations of butyric acid, acting as a potent inhibitor of HDACs and causing histone acetylation. Chromatin immunoprecipitation assays revealed that the corepressor complex containing HDAC1 and AP-4 was dissociated from the HIV-1 long terminal repeat promoter upon stimulation with bacterial culture supernatant concomitantly with the association of acetylated histone and RNA polymerase II. We thus found that P. gingivalis could induce HIV-1 reactivation via chromatin modification and that butyric acid, one of the bacterial metabolites, is responsible for this effect. These results suggest that periodontal diseases could act as a risk factor for HIV-1 reactivation in infected individuals and might contribute to the systemic dissemination of the virus.

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Mode of action of topoisomerase II-targeting agents at a specific DNA sequence

Cited by 112 publications

References 30 publications

Selective inhibition of topoisomerases from Pneumocystis carinii compared with that of topoisomerases from mammalian cells

Selective inhibition of topoisomerases from Pneumocystis carinii compared with that of topoisomerases from mammalian cells

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

Reactivation of Latent HIV-1 Infection by the Periodontopathic Bacterium Porphyromonas gingivalis Involves Histone Modification

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