• Something wrong with this record ?

Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation

E. Jirkovský, A. Jirkovská, H. Bavlovič-Piskáčková, V. Skalická, Z. Pokorná, G. Karabanovich, P. Kollárová-Brázdová, J. Kubeš, O. Lenčová-Popelová, Y. Mazurová, M. Adamcová, AR. Lyon, J. Roh, T. Šimůnek, P. Štěrbová-Kovaříková, M. Štěrba

. 2021 ; 14 (11) : e008209. [pub] 20210923

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22003280

BACKGROUND: Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)-the only drug approved for its prevention-has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept. METHODS: Pharmacokinetically guided study of the cardioprotective effects of clinically used DEX and its chelating metabolite ADR-925 (administered exogenously) was performed together with mechanistic experiments. The cardiotoxicity was induced by daunorubicin in neonatal ventricular cardiomyocytes in vitro and in a chronic rabbit model in vivo (n=50). RESULTS: Intracellular concentrations of ADR-925 in neonatal ventricular cardiomyocytes and rabbit hearts after treatment with exogenous ADR-925 were similar or exceeded those observed after treatment with the parent DEX. However, ADR-925 did not protect neonatal ventricular cardiomyocytes against anthracycline toxicity, whereas DEX exhibited significant protective effects (10-100 µmol/L; P<0.001). Unlike DEX, ADR-925 also had no significant impact on daunorubicin-induced mortality, blood congestion, and biochemical and functional markers of cardiac dysfunction in vivo (eg, end point left ventricular fractional shortening was 32.3±14.7%, 33.5±4.8%, 42.7±1.0%, and 41.5±1.1% for the daunorubicin, ADR-925 [120 mg/kg]+daunorubicin, DEX [60 mg/kg]+daunorubicin, and control groups, respectively; P<0.05). DEX, but not ADR-925, inhibited and depleted TOP2B and prevented daunorubicin-induced genotoxic damage. TOP2B dependency of the cardioprotective effects was probed and supported by experiments with diastereomers of a new DEX derivative. CONCLUSIONS: This study strongly supports a new mechanistic paradigm that attributes clinically effective cardioprotection against anthracycline cardiotoxicity to interactions with TOP2B but not metal chelation and protection against direct oxidative damage.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22003280
003      
CZ-PrNML
005      
20220127150507.0
007      
ta
008      
220113s2021 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1161/CIRCHEARTFAILURE.120.008209 $2 doi
035    __
$a (PubMed)34551586
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Jirkovský, Eduard $u Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic $u Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové (E.J.), Charles University, Czech Republic
245    10
$a Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation / $c E. Jirkovský, A. Jirkovská, H. Bavlovič-Piskáčková, V. Skalická, Z. Pokorná, G. Karabanovich, P. Kollárová-Brázdová, J. Kubeš, O. Lenčová-Popelová, Y. Mazurová, M. Adamcová, AR. Lyon, J. Roh, T. Šimůnek, P. Štěrbová-Kovaříková, M. Štěrba
520    9_
$a BACKGROUND: Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)-the only drug approved for its prevention-has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept. METHODS: Pharmacokinetically guided study of the cardioprotective effects of clinically used DEX and its chelating metabolite ADR-925 (administered exogenously) was performed together with mechanistic experiments. The cardiotoxicity was induced by daunorubicin in neonatal ventricular cardiomyocytes in vitro and in a chronic rabbit model in vivo (n=50). RESULTS: Intracellular concentrations of ADR-925 in neonatal ventricular cardiomyocytes and rabbit hearts after treatment with exogenous ADR-925 were similar or exceeded those observed after treatment with the parent DEX. However, ADR-925 did not protect neonatal ventricular cardiomyocytes against anthracycline toxicity, whereas DEX exhibited significant protective effects (10-100 µmol/L; P<0.001). Unlike DEX, ADR-925 also had no significant impact on daunorubicin-induced mortality, blood congestion, and biochemical and functional markers of cardiac dysfunction in vivo (eg, end point left ventricular fractional shortening was 32.3±14.7%, 33.5±4.8%, 42.7±1.0%, and 41.5±1.1% for the daunorubicin, ADR-925 [120 mg/kg]+daunorubicin, DEX [60 mg/kg]+daunorubicin, and control groups, respectively; P<0.05). DEX, but not ADR-925, inhibited and depleted TOP2B and prevented daunorubicin-induced genotoxic damage. TOP2B dependency of the cardioprotective effects was probed and supported by experiments with diastereomers of a new DEX derivative. CONCLUSIONS: This study strongly supports a new mechanistic paradigm that attributes clinically effective cardioprotection against anthracycline cardiotoxicity to interactions with TOP2B but not metal chelation and protection against direct oxidative damage.
650    _2
$a antracykliny $x škodlivé účinky $x farmakologie $7 D018943
650    _2
$a protinádorová antibiotika $x škodlivé účinky $x farmakologie $7 D000903
650    _2
$a kardiotoxicita $x farmakoterapie $x metabolismus $x prevence a kontrola $7 D066126
650    _2
$a DNA-topoisomerasy typu II $x škodlivé účinky $x metabolismus $7 D004250
650    _2
$a daunomycin $x metabolismus $x farmakologie $7 D003630
650    _2
$a dexrazoxan $x škodlivé účinky $x farmakologie $7 D064730
650    _2
$a nemoci srdce $x farmakoterapie $7 D006331
650    _2
$a srdeční selhání $x farmakoterapie $7 D006333
650    _2
$a lidé $7 D006801
650    _2
$a kardiomyocyty $x účinky léků $x metabolismus $7 D032383
650    _2
$a oxidační stres $x účinky léků $7 D018384
650    _2
$a inhibitory topoisomerasy II $x metabolismus $7 D059005
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Jirkovská, Anna $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic
700    1_
$a Bavlovič-Piskáčková, Hana $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové (H.B.-P., P.Š.-K.), Charles University, Czech Republic
700    1_
$a Skalická, Veronika $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic
700    1_
$a Pokorná, Zuzana $u Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic
700    1_
$a Karabanovich, Galina $u Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové (G.K., J.R.), Charles University, Czech Republic
700    1_
$a Kollárová-Brázdová, Petra $u Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic
700    1_
$a Kubeš, Jan $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic
700    1_
$a Lenčová-Popelová, Olga $u Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic
700    1_
$a Mazurová, Yvona $u Department of Histology and Embryology, Faculty of Medicine in Hradec Králové (Y.M.), Charles University, Czech Republic
700    1_
$a Adamcová, Michaela $u Department of Physiology, Faculty of Medicine in Hradec Králové (M.A.), Charles University, Czech Republic
700    1_
$a Lyon, Alexander R $u Department of Cardiology, Royal Brompton Hospital and Faculty of Medicine, National Heart and Lung Institute, Imperial College London, United Kingdom (A.R.L.)
700    1_
$a Roh, Jaroslav $u Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové (G.K., J.R.), Charles University, Czech Republic
700    1_
$a Šimůnek, Tomáš $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic
700    1_
$a Štěrbová-Kovaříková, Petra $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové (H.B.-P., P.Š.-K.), Charles University, Czech Republic
700    1_
$a Štěrba, Martin $u Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic
773    0_
$w MED00159985 $t Circulation. Heart failure $x 1941-3297 $g Roč. 14, č. 11 (2021), s. e008209
856    41
$u https://pubmed.ncbi.nlm.nih.gov/34551586 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220113 $b ABA008
991    __
$a 20220127150503 $b ABA008
999    __
$a ok $b bmc $g 1750904 $s 1154429
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2021 $b 14 $c 11 $d e008209 $e 20210923 $i 1941-3297 $m Circulation. Heart failure $n Circ Heart Fail $x MED00159985
LZP    __
$a Pubmed-20220113

Find record

Citation metrics

Archiving options