Dexrazoxane is a hydrophilic ring-closed analog of iron chelator ethylenediaminetetraacetic acid and also a strong inhibitor of topoisomerase II with IC50 value of 10µM[1]. Dexrazoxane is the only current FDA approved medication to tackle cardiotoxicity. The mechanism of action in which Dexrazoxane is cardioprotective is by halting necroptosis in cardiomyocytes after anthracycline therapy and concurrently binds with iron and reduces the formation of anthracycline-iron complexes and reactive oxygen species[2].
In vitro, CHO cells were incubated with Dexrazoxane (100µM) for 0.5 or 20h, followed by bleomycin treatment for a further 72h. The cell growth inhibitory effects of bleomycin were unaffected by pretreating CHO cells with Dexrazoxane. Dexrazoxane did not decrease bleomycin-induced inhibition of growth of CHO cells in spite of the ability of the Dexrazoxane metabolite ADR-925 to displace either Fe2+ or Fe3+ from its complex with bleomycin[3]. Neonatal mouse ventricular myocytes (NMVMs) were pretreated with 200µM Dexrazoxane 4h before 0.5µM of doxorubicin hydrochloride treatment, Dexrazoxane exerted a protective effect against doxorubicin-induced cardiotoxicity through attenuating both apoptosis and necroptosis by the inhibition of p38MAPK/NF-kB pathways in cardiomyocytes[4]. HTETOP cells were derived from the human fibrosarcoma cell line HT1080 through the deletion of both endogenous TOP2A alleles and the insertion of a tetracycline-repressible TOP2A transgene. TOP2A-expressing HTETOP cells were treated with 100μM Dexrazoxane for 24h. Dexrazoxane exposure induced topoisomerase IIα (TOP2A)-dependent cell death, γ-H2AX accumulation and increased tail moment in neutral comet assays[5].
In vivo, 6-OHDA induced Parkinson’s disease mouse models were Intraperitoneally administrated with Dexrazoxane (1.5, 5, 15mg/kg/day) for 3 weeks. Dexrazoxane ameliorated dopaminergic neuronal degeneration in Parkinson’s disease models. Dexrazoxane served as a potential neuroprotectant to treat neurotoxin-induced neurodegeneration via attenuation of oxidative stress and ER stress, as well as the suppression of systemic inflammation in both peripheral tissues and brain[6]. Doxorubicin-induced nephropathy rat models was injected intravenously with Dexrazoxane (25mg/kg) once a week for 5 weeks. Dexrazoxane pretreatment markedly raised the survival rate and improved the renal dysfunction in doxorubicin-treated rats. Dexrazoxane ameliorated doxorubicin-induced histopathological lesion of glomerular and tubular and apoptosis. Dexrazoxane restored the oxidant/antioxidant balance via regulating the levels of Malondialdehyde (MDA), superoxide dismutase (SOD), and antioxidant capacity[7].
References:
[1] Hasinoff B B, Herman E H. Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovasc Toxicol. 2007;7(2):140-4.
[2] Rahimi P, Barootkoob B, ElHashash A, Nair A. et al. Efficacy of dexrazoxane in Cardiac Protection in Pediatric Patients Treated With Anthracyclines. Cureus. 2023 Apr 8;15(4):e37308.
[3] Xing Wu X, Patel D, Hasinoff B B, et al. The iron chelating cardioprotective prodrug dexrazoxane does not affect the cell growth inhibitory effects of bleomycin. J Inorg Biochem. 2004 Nov;98(11):1818-23.
[4] Yu X X, Ruan Y, Huang X Q, et al. Dexrazoxane ameliorates doxorubicin-induced cardiotoxicity by inhibiting both apoptosis and necroptosis in cardiomyocytes. Biochem Biophys Res Commun. 2020 Feb 26;523(1):140-146.
[5] Deng S, Yan T D, Nikolova T, et al. The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF3 and the DNA damage response in cancer cells. Br J Pharmacol. 2015 May;172(9):2246-57.
[6] Mei M, Zhou Y Z, Liu M D, et al. Antioxidant and anti-inflammatory effects of dexrazoxane on dopaminergic neuron degeneration in rodent models of Parkinson's disease. Neuropharmacology. 2019 Dec 1;160:107758.
[7] Hu H H, Xie C P, Weng Z P, et al. Dexrazoxane Alleviated Doxorubicin-Induced Nephropathy in Rats. Pharmacology. 2022;107(3-4):206-215.
Dexrazoxane是亲水性闭环结构的铁螯合剂乙二胺四乙酸类似物，同时也是拓扑异构酶Ⅱ的强效抑制剂，IC50值为10µM[1]。Dexrazoxane是目前唯一获FDA批准用于对抗蒽环类药物心脏毒性的药物，其心脏保护机制为阻断蒽环类治疗后心肌细胞的坏死性凋亡，同时与铁结合，减少蒽环类-铁复合物及活性氧生成[2]。
体外实验中，CHO细胞与Dexrazoxane（100µM）孵育0.5或20h，随后再用博来霉素处理72h。尽管Dexrazoxane代谢产物ADR-925能从博来霉素-铁复合物中置换Fe2+或Fe3+，但CHO细胞经Dexrazoxane预处理并未减弱博来霉素的生长抑制作用[3]。新生小鼠心室肌细胞（NMVMs）在0.5µM盐酸阿霉素处理前4h用200µM Dexrazoxane预处理，Dexrazoxane通过抑制p38MAPK/NF-κB通路减轻阿霉素诱导的心肌细胞凋亡与坏死性凋亡，从而发挥心脏保护作用[4]。HTETOP细胞系来源于人纤维肉瘤HT1080细胞，通过敲除内源TOP2A双等位基因并插入可四环素调控的TOP2A转座子构建。表达TOP2A的HTETOP细胞经100μM Dexrazoxane处理24h后，Dexrazoxane诱导拓扑异构酶Ⅱα（TOP2A）依赖性细胞死亡，γ-H2AX积聚，并在中性彗星实验中尾矩增加[5]。
体内实验中，6-OHDA诱导的帕金森病小鼠模型腹腔注射Dexrazoxane（1.5、5、15mg/kg/day）3周。Dexrazoxane改善帕金森病模型中多巴胺能神经元退变，通过减轻氧化应激与内质网应激，并抑制外周组织及脑部系统性炎症，成为治疗神经毒素诱导神经退变的潜在神经保护剂[6]。阿霉素诱导的肾病大鼠模型每周静脉注射Dexrazoxane（25mg/kg），持续5周。Dexrazoxane预处理显著提高存活率并改善阿霉素诱导的肾功能不全，减轻阿霉素诱导的肾小球及小管组织病理损伤与细胞凋亡；Dexrazoxane通过调节丙二醛（MDA）、超氧化物歧化酶（SOD）及抗氧化能力，恢复氧化/抗氧化平衡[7]。