Jirkovský Eduard, Jirkovská Anna, Bavlovič-Piskáčková Hana, Skalická Veronika, Pokorná Zuzana, Karabanovich Galina, Kollárová-Brázdová Petra, Kubeš Jan, Lenčová-Popelová Olga, Mazurová Yvona, Adamcová Michaela, Lyon Alexander R, Roh Jaroslav, Šimůnek Tomáš, Štěrbová-Kovaříková Petra, Štěrba Martin
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.
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové (E.J.), Charles University, Czech Republic.
Circ Heart Fail. 2021 Nov;14(11):e008209. doi: 10.1161/CIRCHEARTFAILURE.120.008209. Epub 2021 Sep 23.
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.
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).
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; <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; <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.
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.
传统上认为蒽环类药物引起的心力衰竭是由于直接的铁催化氧化损伤。右丙亚胺（DEX）是唯一被批准用于预防该疾病的药物，一直被认为是通过其铁螯合代谢产物ADR-925来保护心脏。然而，缺乏直接证据，并且最近提出的拓扑异构酶IIβ（TOP2B）假说对最初的概念提出了挑战。
进行了临床使用的DEX及其螯合代谢产物ADR-925（外源性给药）心脏保护作用的药代动力学指导研究以及机制实验。体外在新生心室心肌细胞中以及体内在慢性兔模型中（n = 50）用柔红霉素诱导心脏毒性。
用外源性ADR-925处理后，新生心室心肌细胞和兔心脏中ADR-925的细胞内浓度与用母体DEX处理后观察到的浓度相似或更高。然而，ADR-925并不能保护新生心室心肌细胞免受蒽环类药物毒性，而DEX则表现出显著的保护作用（10 - 100 μmol/L；<0.001）。与DEX不同，ADR-925对柔红霉素诱导的死亡率、血液充血以及体内心脏功能障碍的生化和功能标志物也没有显著影响（例如，柔红霉素组、ADR-925 [120 mg/kg] + 柔红霉素组、DEX [60 mg/kg] + 柔红霉素组和对照组的终点左心室缩短分数分别为32.3±14.7%、33.5±4.8%、42.7±1.0%和41.5±1.1%；<0.05）。DEX而非ADR-925抑制并消耗TOP2B，并预防柔红霉素诱导的基因毒性损伤。通过一种新的DEX衍生物的非对映异构体实验探究并支持了心脏保护作用对TOP2B的依赖性。
本研究强烈支持一种新的机制范式，即临床上有效的针对蒽环类药物心脏毒性的心脏保护作用归因于与TOP2B的相互作用，而非金属螯合和对直接氧化损伤的保护。
