Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue

Chêne, Patrick; Rudloff, Joëlle; Schoepfer, Joseph; Furet, Pascal; Meier, Peter J.; Qian, Zhiyan; Schlaeppi, Jean Marc; Schmitz, Rita; Radimerski, Thomas

doi:10.1186/1472-6769-9-1

Cited by 74 publications

(69 citation statements)

References 45 publications

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“…2A). Consistent with previous reports (Morris et al, 2000;Chène et al, 2009), the closed clamp inhibitor ICRF-193 also reduced topo IIa-mediated ATP hydrolysis ( Fig. 2A).…”

Section: Resultssupporting

confidence: 92%

Salicylate, a Catalytic Inhibitor of Topoisomerase II, Inhibits DNA Cleavage and Is Selective for the α Isoform

et al. 2013

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Topoisomerase II (topo II) is a ubiquitous enzyme that is essential for cell survival through its role in regulating DNA topology and chromatid separation. Topo II can be poisoned by common chemotherapeutics (such as doxorubicin and etoposide), leading to the accumulation of cytotoxic enzyme-linked DNA doublestranded breaks. In contrast, nonbreak-inducing topo II catalytic inhibitors have also been described and have more limited use in clinical chemotherapy. These agents, however, may alter the efficacy of regimens incorporating topo II poisons. We previously identified salicylate, the primary metabolite of aspirin, as a novel catalytic inhibitor of topo II. We have now determined the mechanism by which salicylate inhibits topo II. As catalytic inhibitors can act at a number of steps in the topo II catalytic cycle, we used multiple independent, biochemical approaches to interrogate the catalytic cycle. Furthermore, as mammalian cells express two isoforms of topo II (a and b), we examined whether salicylate was isoform selective. Our results demonstrate that salicylate is unable to intercalate DNA, and does not prevent enzyme-DNA interaction, nor does it promote stabilization of topo IIa in closed clamps on DNA. Although salicylate decreased topo IIa ATPase activity in a dose-dependent noncompetitive manner, this was secondary to salicylate-mediated inhibition of DNA cleavage. Surprisingly, comparison of salicylate's effects using purified human topo IIa and topo IIb revealed that salicylate selectively inhibits the a isoform. These findings provide a definitive mechanism for salicylate-mediated inhibition of topo IIa and provide support for further studies determining the basis for its isoform selectivity.

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“…2A). Consistent with previous reports (Morris et al, 2000;Chène et al, 2009), the closed clamp inhibitor ICRF-193 also reduced topo IIa-mediated ATP hydrolysis ( Fig. 2A).…”

Section: Resultssupporting

confidence: 92%

Salicylate, a Catalytic Inhibitor of Topoisomerase II, Inhibits DNA Cleavage and Is Selective for the α Isoform

et al. 2013

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“…Recent studies reported the synthesis of new derivatives such as the purine analog quinoline aminopurine compound 1 (Chène et al, 2009), thiosemicarbazones (Huang et al, 2010), N-fused imidazoles (Baviskar et al, 2011), or xanthone analogs (Jun et al, 2011), which inhibit the catalytic activity of Top2␣ by an ATPcompetitive mechanism. Apart from quinoline aminopurine compound 1, which inhibits both isoforms (Chène et al, 2009), it is not known whether these derivatives also inhibit the catalytic activity of Top2␤, which is expressed in postmitotic cells (Watanabe et al, 1994;Lyu and Wang, 2003) and nonproliferating tissues such as the adult heart (Capranico et al, 1992). Development of a selective Top2␣ catalytic inhibitor would therefore be useful because Top2␤ was shown to be involved in anthracyclin-induced cardiotoxicity and was also required for neuronal differentiation and the expression of a number of neuronal genes (Lyu and Wang, 2003;Nur-EKamal et al, 2007).…”

Section: Top2α Top2βmentioning

confidence: 99%

The Polyphenolic Ellagitannin Vescalagin Acts As a Preferential Catalytic Inhibitor of the α Isoform of Human DNA Topoisomerase II

Auzanneau¹,

Montaudon²,

Jacquet³

et al. 2012

Mol Pharmacol

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Polyphenolic ellagitannins are natural compounds that are often associated with the therapeutic activity of plant extracts used in traditional medicine. They display cancer-preventing activity in animal models by a mechanism that remains unclear. Potential targets have been proposed, including DNA topoisomerases II (Top2). Top2␣ and Top2␤, the two isoforms of the human Top2, play a crucial role in the regulation of replication, transcription, and chromosome segregation. They are the target of anticancer agents used in the clinic such as anthracyclines (e.g., doxorubicin) or the epipodophyllotoxin etoposide. It was recently shown that the antitumor activity of etoposide was due primarily to the inhibition of Top2␣, whereas inhibition of Top2␤ was responsible for the development of secondary malignancies, pointing to the need for more selective Top2␣ inhibitors. Here, we show that the polyphenolic ellagitannin vescalagin preferentially inhibits the decatenation activity of Top2␣ in vitro, by a redox-independent mechanism. In CEM cells, we also show that transient small interfering RNA-mediated downregulation of Top2␣ but not of Top2␤ conferred a resistance to vescalagin, indicating that the ␣ isoform is a preferential target. We further confirmed that Top2␣ inhibition was due to a catalytic inhibition of the enzyme because it did not induce DNA double-strand breaks in CEM-treated cells but prevented the formation of Top2␣-rather than Top2␤-DNA covalent complexes induced by etoposide. To our knowledge, vescalagin is the first example of a catalytic inhibitor for which cytotoxicity is due, at least in part, to the preferential inhibition of Top2␣.

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“…Activity against topoisomerase II was done as previously described (24). The activity of NVP-BEP800 was evaluated against a panel of kinases consisting of HER-1, KDR, Flt-3, IGF-1R, Tek, c-src, c-Met, Ret, JAK-2, EphB4, FGFR-3-K650E, Axl, FAK, c-Abl, c-Abl-T315I, PKA, CDK1/B, PKB/Akt, PDK1, and B-Raf-V599E.…”

Section: Hsp90 Binding and Selectivity Assaysmentioning

confidence: 99%

Preclinical Antitumor Activity of the Orally Available Heat Shock Protein 90 Inhibitor NVP-BEP800

Massey

Schoepfer

Brough

et al. 2010

Molecular Cancer Therapeutics

Self Cite

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Heat shock protein 90 (Hsp90) is a ubiquitously expressed molecular chaperone with ATPase activity involved in the conformational maturation and stability of key signaling molecules involved in cell proliferation, survival, and transformation. Through its ability to modulate multiple pathways involved in oncogenesis, Hsp90 has generated considerable interest as a therapeutic target. NVP-BEP800 is a novel, fully synthetic, orally bioavailable inhibitor that binds to the NH 2 -terminal ATP-binding pocket of Hsp90. NVP-BEP800 showed activity against a panel of human tumor cell lines and primary human xenografts in vitro at nanomolar concentrations. In A375 melanoma and BT-474 breast cancer cell lines, NVP-BEP800 induced client protein degradation (including ErbB2, B-Raf V600E , Raf-1, and Akt) and Hsp70 induction. Oral administration of NVP-BEP800 was well tolerated and induced robust antitumor responses in tumor xenograft models, including regression in the BT-474 breast cancer model. In these tumor models, NVP-BEP800 modulated Hsp90 client proteins and downstream signaling pathways at doses causing antitumor activity. NVP-BEP800 showed in vivo activity in a variety of dosing regimens covering daily to weekly schedules, potentially providing a high degree of flexibility in dose and schedule within the clinical setting. Overall, given the mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, NVP-BEP800 is an exciting new oral Hsp90 inhibitor warranting further development.

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Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue

Cited by 74 publications

References 45 publications

Salicylate, a Catalytic Inhibitor of Topoisomerase II, Inhibits DNA Cleavage and Is Selective for the α Isoform

Salicylate, a Catalytic Inhibitor of Topoisomerase II, Inhibits DNA Cleavage and Is Selective for the α Isoform

The Polyphenolic Ellagitannin Vescalagin Acts As a Preferential Catalytic Inhibitor of the α Isoform of Human DNA Topoisomerase II

Preclinical Antitumor Activity of the Orally Available Heat Shock Protein 90 Inhibitor NVP-BEP800

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