Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and Catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle
Identifieur interne : 000087 ( PascalFrancis/Corpus ); précédent : 000086; suivant : 000088Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and Catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle
Auteurs : M. Sehested ; P. B. JensenSource :
- Biochemical pharmacology [ 0006-2952 ] ; 1996.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
The complex catalytic cycle of topoisomerase II is the target of important antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin, inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled cell kill is susceptible to pharmacological regulation by drugs interfering with other steps in the enzyme's catalytic cycle (i.e. so-called catalytic inhibitors). From in vitro studies, it appears that there are 2 distinct sites in the cycle at which a complete antagonism of the toxicity of topoisomerase II poisons can be obtained. The first is the inhibition of the enzyme's binding to its DNA substrate as seen with intercalating drugs such as chloroquine and aclarubicin ; a second, more specific, interaction is elicited by bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II in the form of a closed bracelet surrounding the DNA at the postreligation step. To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCl nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and aclarubicin. With ICRF-187, we found a reversible ATP dependent decrease in the extractable levels of both the α and the β isoforms of topoisomerase II. In contrast to ICRF-187, aclarubicin increased the amount of extractable enzyme from cells. Further, when using the terpenoid clerocidin, which differs from conventional topoisomerase II poisons by forming a salt- and heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on formation of DNA strand breaks and cytotoxicity. However, aclarubicin, which interferes early in the topoisomerase II catalytic cycle, was able to antagonize DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4 different steps in the topoisomerase II cycle that can be uncoupled in the cell by different drug types : etoposide and clerocidin cause reversible and irreversible inhibition of DNA resealing, respectively, and DNA intercalating agents, such as aclarubicin, inhibit binding of topoisomerase II enzyme to its DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy dependent inappropriate binding of topoisomerase II to DNA after the resealing step. This knowledge may enable the design of rational combinations of topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of anticancer therapy.
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Pour connaître la documentation sur le format Inist Standard.
pA |
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Format Inist (serveur)
NO : | PASCAL 96-0211507 INIST |
---|---|
ET : | Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and Catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle |
AU : | SEHESTED (M.); JENSEN (P. B.) |
AF : | Department of Pathology, Sundby Hospital/2300 Copenhangen/Danemark (1 aut.) |
DT : | Publication en série; Niveau analytique |
SO : | Biochemical pharmacology; ISSN 0006-2952; Coden BCPCA6; Royaume-Uni; Da. 1996; Vol. 51; No. 7; Pp. 879-886; Bibl. 30 ref. |
LA : | Anglais |
EA : | The complex catalytic cycle of topoisomerase II is the target of important antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin, inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled cell kill is susceptible to pharmacological regulation by drugs interfering with other steps in the enzyme's catalytic cycle (i.e. so-called catalytic inhibitors). From in vitro studies, it appears that there are 2 distinct sites in the cycle at which a complete antagonism of the toxicity of topoisomerase II poisons can be obtained. The first is the inhibition of the enzyme's binding to its DNA substrate as seen with intercalating drugs such as chloroquine and aclarubicin ; a second, more specific, interaction is elicited by bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II in the form of a closed bracelet surrounding the DNA at the postreligation step. To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCl nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and aclarubicin. With ICRF-187, we found a reversible ATP dependent decrease in the extractable levels of both the α and the β isoforms of topoisomerase II. In contrast to ICRF-187, aclarubicin increased the amount of extractable enzyme from cells. Further, when using the terpenoid clerocidin, which differs from conventional topoisomerase II poisons by forming a salt- and heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on formation of DNA strand breaks and cytotoxicity. However, aclarubicin, which interferes early in the topoisomerase II catalytic cycle, was able to antagonize DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4 different steps in the topoisomerase II cycle that can be uncoupled in the cell by different drug types : etoposide and clerocidin cause reversible and irreversible inhibition of DNA resealing, respectively, and DNA intercalating agents, such as aclarubicin, inhibit binding of topoisomerase II enzyme to its DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy dependent inappropriate binding of topoisomerase II to DNA after the resealing step. This knowledge may enable the design of rational combinations of topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of anticancer therapy. |
CC : | 002B02R02 |
FD : | Etoposide; Aclarubicine; Dexrazoxane; DNA; Mécanisme action; Activité biologique; In vitro; Association médicamenteuse; Lignée cellulaire; Inhibiteur enzyme; DNA topoisomerase (ATP-hydrolysing); ICFF 187; Clérocidine; Podophyllotoxine dérivé |
FG : | Anticancéreux; Antimitotique; Anthracyclines; Antibiotique; Pipérazine dérivé; Isomerases; Enzyme |
ED : | DNA; Mechanism of action; Biological activity; In vitro; Drug combination; Cell line; Enzyme inhibitor; DNA topoisomerase (ATP-hydrolysing) |
EG : | Antineoplastic agent; Antimitotic; Anthracyclins; Antibiotic; Piperazine derivatives; Isomerases; Enzyme |
SD : | DNA; Mecanismo acción; Actividad biológica; In vitro; Asociación medicamentosa; Línea celular; Inhibidor enzima; DNA topoisomerase (ATP-hydrolysing) |
LO : | INIST-1418.354000044708950020 |
ID : | 96-0211507 |
Links to Exploration step
Pascal:96-0211507Le document en format XML
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<author><name sortKey="Sehested, M" sort="Sehested, M" uniqKey="Sehested M" first="M." last="Sehested">M. Sehested</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and Catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle</title>
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<front><div type="abstract" xml:lang="en">The complex catalytic cycle of topoisomerase II is the target of important antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin, inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled cell kill is susceptible to pharmacological regulation by drugs interfering with other steps in the enzyme's catalytic cycle (i.e. so-called catalytic inhibitors). From in vitro studies, it appears that there are 2 distinct sites in the cycle at which a complete antagonism of the toxicity of topoisomerase II poisons can be obtained. The first is the inhibition of the enzyme's binding to its DNA substrate as seen with intercalating drugs such as chloroquine and aclarubicin ; a second, more specific, interaction is elicited by bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II in the form of a closed bracelet surrounding the DNA at the postreligation step. To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCl nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and aclarubicin. With ICRF-187, we found a reversible ATP dependent decrease in the extractable levels of both the α and the β isoforms of topoisomerase II. In contrast to ICRF-187, aclarubicin increased the amount of extractable enzyme from cells. Further, when using the terpenoid clerocidin, which differs from conventional topoisomerase II poisons by forming a salt- and heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on formation of DNA strand breaks and cytotoxicity. However, aclarubicin, which interferes early in the topoisomerase II catalytic cycle, was able to antagonize DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4 different steps in the topoisomerase II cycle that can be uncoupled in the cell by different drug types : etoposide and clerocidin cause reversible and irreversible inhibition of DNA resealing, respectively, and DNA intercalating agents, such as aclarubicin, inhibit binding of topoisomerase II enzyme to its DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy dependent inappropriate binding of topoisomerase II to DNA after the resealing step. This knowledge may enable the design of rational combinations of topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of anticancer therapy.</div>
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<fC01 i1="01" l="ENG"><s0>The complex catalytic cycle of topoisomerase II is the target of important antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin, inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled cell kill is susceptible to pharmacological regulation by drugs interfering with other steps in the enzyme's catalytic cycle (i.e. so-called catalytic inhibitors). From in vitro studies, it appears that there are 2 distinct sites in the cycle at which a complete antagonism of the toxicity of topoisomerase II poisons can be obtained. The first is the inhibition of the enzyme's binding to its DNA substrate as seen with intercalating drugs such as chloroquine and aclarubicin ; a second, more specific, interaction is elicited by bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II in the form of a closed bracelet surrounding the DNA at the postreligation step. To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCl nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and aclarubicin. With ICRF-187, we found a reversible ATP dependent decrease in the extractable levels of both the α and the β isoforms of topoisomerase II. In contrast to ICRF-187, aclarubicin increased the amount of extractable enzyme from cells. Further, when using the terpenoid clerocidin, which differs from conventional topoisomerase II poisons by forming a salt- and heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on formation of DNA strand breaks and cytotoxicity. However, aclarubicin, which interferes early in the topoisomerase II catalytic cycle, was able to antagonize DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4 different steps in the topoisomerase II cycle that can be uncoupled in the cell by different drug types : etoposide and clerocidin cause reversible and irreversible inhibition of DNA resealing, respectively, and DNA intercalating agents, such as aclarubicin, inhibit binding of topoisomerase II enzyme to its DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy dependent inappropriate binding of topoisomerase II to DNA after the resealing step. This knowledge may enable the design of rational combinations of topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of anticancer therapy.</s0>
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<s5>16</s5>
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<server><NO>PASCAL 96-0211507 INIST</NO>
<ET>Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and Catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle</ET>
<AU>SEHESTED (M.); JENSEN (P. B.)</AU>
<AF>Department of Pathology, Sundby Hospital/2300 Copenhangen/Danemark (1 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Biochemical pharmacology; ISSN 0006-2952; Coden BCPCA6; Royaume-Uni; Da. 1996; Vol. 51; No. 7; Pp. 879-886; Bibl. 30 ref.</SO>
<LA>Anglais</LA>
<EA>The complex catalytic cycle of topoisomerase II is the target of important antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin, inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled cell kill is susceptible to pharmacological regulation by drugs interfering with other steps in the enzyme's catalytic cycle (i.e. so-called catalytic inhibitors). From in vitro studies, it appears that there are 2 distinct sites in the cycle at which a complete antagonism of the toxicity of topoisomerase II poisons can be obtained. The first is the inhibition of the enzyme's binding to its DNA substrate as seen with intercalating drugs such as chloroquine and aclarubicin ; a second, more specific, interaction is elicited by bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II in the form of a closed bracelet surrounding the DNA at the postreligation step. To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCl nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and aclarubicin. With ICRF-187, we found a reversible ATP dependent decrease in the extractable levels of both the α and the β isoforms of topoisomerase II. In contrast to ICRF-187, aclarubicin increased the amount of extractable enzyme from cells. Further, when using the terpenoid clerocidin, which differs from conventional topoisomerase II poisons by forming a salt- and heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on formation of DNA strand breaks and cytotoxicity. However, aclarubicin, which interferes early in the topoisomerase II catalytic cycle, was able to antagonize DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4 different steps in the topoisomerase II cycle that can be uncoupled in the cell by different drug types : etoposide and clerocidin cause reversible and irreversible inhibition of DNA resealing, respectively, and DNA intercalating agents, such as aclarubicin, inhibit binding of topoisomerase II enzyme to its DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy dependent inappropriate binding of topoisomerase II to DNA after the resealing step. This knowledge may enable the design of rational combinations of topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of anticancer therapy.</EA>
<CC>002B02R02</CC>
<FD>Etoposide; Aclarubicine; Dexrazoxane; DNA; Mécanisme action; Activité biologique; In vitro; Association médicamenteuse; Lignée cellulaire; Inhibiteur enzyme; DNA topoisomerase (ATP-hydrolysing); ICFF 187; Clérocidine; Podophyllotoxine dérivé</FD>
<FG>Anticancéreux; Antimitotique; Anthracyclines; Antibiotique; Pipérazine dérivé; Isomerases; Enzyme</FG>
<ED>DNA; Mechanism of action; Biological activity; In vitro; Drug combination; Cell line; Enzyme inhibitor; DNA topoisomerase (ATP-hydrolysing)</ED>
<EG>Antineoplastic agent; Antimitotic; Anthracyclins; Antibiotic; Piperazine derivatives; Isomerases; Enzyme</EG>
<SD>DNA; Mecanismo acción; Actividad biológica; In vitro; Asociación medicamentosa; Línea celular; Inhibidor enzima; DNA topoisomerase (ATP-hydrolysing)</SD>
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<ID>96-0211507</ID>
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