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Research ArticleCardiovascular

Investigation of Structure-Activity Relationships of Dexrazoxane Analogs Reveals Topoisomerase IIβ Interaction as a Prerequisite for Effective Protection against Anthracycline Cardiotoxicity

Petra Kollárová-Brázdová, Anna Jirkovská, Galina Karabanovich, Zuzana Pokorná, Hana Bavlovič Piskáčková, Eduard Jirkovský, Jan Kubeš, Olga Lenčová-Popelová, Yvona Mazurová, Michaela Adamcová, Veronika Skalická, Petra Štěrbová-Kovaříková, Jaroslav Roh, Tomáš Šimůnek and Martin Štěrba
Journal of Pharmacology and Experimental Therapeutics June 2020, 373 (3) 402-415; DOI: https://doi.org/10.1124/jpet.119.264580
Petra Kollárová-Brázdová
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Anna Jirkovská
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Galina Karabanovich
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Zuzana Pokorná
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Hana Bavlovič Piskáčková
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Eduard Jirkovský
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Jan Kubeš
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Olga Lenčová-Popelová
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Yvona Mazurová
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Michaela Adamcová
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Veronika Skalická
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Petra Štěrbová-Kovaříková
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Jaroslav Roh
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Tomáš Šimůnek
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Martin Štěrba
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Abstract

Bisdioxopiperazine agent dexrazoxane (ICRF-187) has been the only effective and approved drug for prevention of chronic anthracycline cardiotoxicity. However, the structure-activity relationships (SARs) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogs and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that dexrazoxane derivatives exert cardioprotection via metal chelation and/or modulation of topoisomerase IIβ (Top2B) activity in chronic anthracycline cardiotoxicity. Dexrazoxane was alkylated in positions that should not interfere with the metal-chelating mechanism of cardioprotective action; that is, on dioxopiperazine imides or directly on the dioxopiperazine ring. The protective effects of these agents were assessed in vitro in neonatal cardiomyocytes. All studied modifications of dexrazoxane molecule, including simple methylation, were found to abolish the cardioprotective effects. Because this challenged the prevailing mechanistic concept and previously reported data, the two closest derivatives [(±)-4,4'-(propane-1,2-diyl)bis(1-methylpiperazine-2,6-dione) and 4-(2-(3,5-dioxopiperazin-1-yl)ethyl)-3-methylpiperazine-2,6-dione] were thoroughly scrutinized in vivo using a rabbit model of chronic anthracycline cardiotoxicity. In contrast to dexrazoxane, both compounds failed to protect the heart, as demonstrated by mortality, cardiac dysfunction, and myocardial damage parameters, although the pharmacokinetics and metal-chelating properties of their metabolites were comparable to those of dexrazoxane. The loss of cardiac protection was shown to correlate with their abated potential to inhibit and deplete Top2B both in vitro and in vivo. These findings suggest a very tight SAR between bisdioxopiperazine derivatives and their cardioprotective effects and support Top2B as a pivotal upstream druggable target for effective cardioprotection against anthracycline cardiotoxicity.

SIGNIFICANCE STATEMENT This study has revealed the previously unexpected tight structure-activity relationships of cardioprotective effects in derivatives of dexrazoxane, which is the only drug approved for the prevention of cardiomyopathy and heart failure induced by anthracycline anticancer drugs. The data presented in this study also strongly argue against the importance of metal-chelating mechanisms for the induction of this effect and support the viability of topoisomerase IIβ as an upstream druggable target for effective and clinically translatable cardioprotection.

Footnotes

    • Received December 19, 2019.
    • Accepted March 23, 2020.
  • This study was supported by the Charles University Grant Agency (GAUK) 680216; Czech Science Foundation (GAČR) 18-08169S; Charles University Research Program Progres [Grant Q40/5]; and by project Pre-application research into innovative medicines and medical technologies (InoMed) reg. No. CZ.02.1.01/0.0/0.0/18_069/0010046 co-funded by the European Union.

  • Conflict of interest: None declared.

  • https://doi.org/10.1124/jpet.119.264580.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 373 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 373, Issue 3
1 Jun 2020
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Research ArticleCardiovascular

DEX Structure-Activity Relationships and Cardioprotection

Petra Kollárová-Brázdová, Anna Jirkovská, Galina Karabanovich, Zuzana Pokorná, Hana Bavlovič Piskáčková, Eduard Jirkovský, Jan Kubeš, Olga Lenčová-Popelová, Yvona Mazurová, Michaela Adamcová, Veronika Skalická, Petra Štěrbová-Kovaříková, Jaroslav Roh, Tomáš Šimůnek and Martin Štěrba
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 402-415; DOI: https://doi.org/10.1124/jpet.119.264580

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Research ArticleCardiovascular

DEX Structure-Activity Relationships and Cardioprotection

Petra Kollárová-Brázdová, Anna Jirkovská, Galina Karabanovich, Zuzana Pokorná, Hana Bavlovič Piskáčková, Eduard Jirkovský, Jan Kubeš, Olga Lenčová-Popelová, Yvona Mazurová, Michaela Adamcová, Veronika Skalická, Petra Štěrbová-Kovaříková, Jaroslav Roh, Tomáš Šimůnek and Martin Štěrba
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 402-415; DOI: https://doi.org/10.1124/jpet.119.264580
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