Human small cell lung cancer NYH cells resistant to the bisdioxopiperazine ICRF‐187 exhibit a functional dominant Tyr165Ser mutation in the Walker A ATP binding site of topoisomerase IIα

Wessel, Irene; Jensen, Lars H.; Renodon-Cornière, Axelle; Sørensen, Tina K.; Nitiss, John L.; Jensen, Peter Buhl; Sehested, Maxwell

doi:10.1016/s0014-5793(02)02805-3

Cited by 32 publications

(59 citation statements)

References 12 publications

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“…We have identified previously two mutations in human topoisomerase II, R162Q (Wessel et al, 1999) and L169F (Jensen et al, 2000b;Patel et al, 2000), that confer resistance to ICRF-193 and ICRF-187 when functionally expressed in JN394t2-4 yeast cells. To investigate the role of these residues in the bisdioxopiperazine protein interaction, we examined the effect of other amino-acid substitutions at these positions.…”

Section: Resultsmentioning

confidence: 99%

“…Site-directed mutagenesis was carried out using a quick-change kit (Stratagene, La Jolla, CA) as described by Sehested et al (1998). Primers used to construct the R162Q and L169F mutations are described by Wessel et al (1999) and Jensen et al (2000b). Other primers used in site-directed mutagenesis are depicted in Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…On the other hand, a core fragment of Drosophila melanogaster topoisomerase II lacking the N-terminal clamp region was clearly capable of forming a salt-stable closed-clamp complex on DNA (Chang et al, 1998), indicating that the core region is also involved. Mutational analysis also points to the involvement of both the N-terminal and core region in the bisdioxopiperazine interaction because resistance-conferring mutations are found in both regions of the enzyme Wessel et al, 1999Jensen et al, 2000b;Patel et al, 2000).…”

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confidence: 99%

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Probing the Role of Linker Substituents in Bisdioxopiperazine Analogs for Activity against Wild-Type and Mutant Human Topoisomerase IIα

et al. 2003

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The bisdioxopiperazines are catalytic inhibitors of eukaryotic type II DNA topoisomerases capable of trapping these enzymes as a salt-stable closed-clamp complex on circular DNA. The various bisdioxopiperazine analogs differ from each other because of structural differences in the linker connecting the two dioxopiperazine rings. Although the composition of this linker region has been found to be important for potency, the structural basis for this is largely unknown. To elucidate the role of the linker region in drug action, we have analyzed the effect of different linker substituents in otherwise identical analogs by studying their interaction with wild-type and mutant human topoisomerase II␣. Two mutations, L169I and R162Q, displayed differential sensitivity toward closely related analogs, suggesting that the linker region in these compounds plays a highly specific role in protein drug interaction. The finding that the L169I mutation, which probably represents a subtle structural change, was sufficient to confer resistance further emphases the importance of this region of the protein for bisdioxopiperazine inhibition of topoisomerase II. Comparing the sensitivity profiles of different bisdioxopiperazines against wildtype and mutant proteins with that of mitindomide, we observed a spectrum of sensitivity closely resembling that of ICRF-154, a bisdioxopiperazine with no linker substituents. We discuss the implications of these observations for the understanding of the mechanism of bisdioxopiperazine action on topoisomerase II.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Probing the Role of Linker Substituents in Bisdioxopiperazine Analogs for Activity against Wild-Type and Mutant Human Topoisomerase IIα

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“…This conserved motif is important for the binding of ATP, as well as for the catalytic inhibitors acting on the ATPase domain (27). This notion is supported by a site-directed mutagenesis result showing that the mutations in Arg162Gln and Tyr165Ser in the ATP binding site lead to drug resistance (37,38). These observations, consistent with the results of the DNA decatenation assay and the malachite green assay, support the idea that (ϩ)-rutamarin functions as a Topo II␣ catalytic inhibitor.…”

Section: (؉)-Rutamarin Inhibits the Lytic Replication Of Kshvmentioning

confidence: 86%

Antiviral Activity of (+)-Rutamarin against Kaposi's Sarcoma-Associated Herpesvirus by Inhibition of the Catalytic Activity of Human Topoisomerase II

González-Molleda

Yan

et al. 2014

Antimicrob Agents Chemother

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“…22 with modifications described in ref. 23 and was purified to >95% purity as judged by SDS-PAGE and Coomassie blue staining.…”

Section: Methodsmentioning

confidence: 99%

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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Human small cell lung cancer NYH cells resistant to the bisdioxopiperazine ICRF‐187 exhibit a functional dominant Tyr165Ser mutation in the Walker A ATP binding site of topoisomerase IIα

Cited by 32 publications

References 12 publications

Probing the Role of Linker Substituents in Bisdioxopiperazine Analogs for Activity against Wild-Type and Mutant Human Topoisomerase IIα

Probing the Role of Linker Substituents in Bisdioxopiperazine Analogs for Activity against Wild-Type and Mutant Human Topoisomerase IIα

Antiviral Activity of (+)-Rutamarin against Kaposi's Sarcoma-Associated Herpesvirus by Inhibition of the Catalytic Activity of Human Topoisomerase II

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

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