IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-11-30 DOI:10.1016/j.jpet.2024.100048
Mohammad Zulkifli, Krishna P Maremanda, Adriana U Okonkwo, Ifrah Farid, Vishal M Gohil
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引用次数: 0

摘要

铜(Cu)是金属酶(如线粒体电子传递链的末端酶细胞色素 c 氧化酶(CcO))所必需的辅助因子。直接或间接阻止铜向线粒体运输的突变会导致致命的儿科疾病,如门克氏病。目前尚无临床批准的治疗门克思病的方法。我们最近发现,一种正在研究的化疗药物伊利司莫(ES)在与 Cu 复合物(ES-Cu)复配后,能挽救线粒体 Cu 缺乏症,激活 CcO,并防止门克氏症小鼠模型的围产期致死。然而,ES-Cu 也有可能引发杯突症(一种依赖 Cu 的细胞死亡)。因此,要将 ES-Cu 开发为治疗梅克斯病的药物,关键是要确定 ES-Cu 在缺铜模型中的治疗指数。为此,我们使用缺铜大鼠心肌细胞系和斑驳小鼠重症门克氏症模型来确定 ES-Cu 的毒性和疗效。我们的细胞培养研究表明,ES-Cu 的 EC50 比 IC50 低 50 倍。此外,铜毒性的生物标志物,包括脂酰化蛋白和线粒体含铁硫簇蛋白子集,只有在使用 ES-Cu 的浓度比其 EC50 高 10 至 25 倍时才会被激活。重要的是,在使用治疗剂量的 ES-Cu 治疗斑驳小鼠时,这些生物标志物均未被激活。我们的研究表明,ES-Cu 在体外和体内都能将铜输送到 CcO,而不会引发杯突变,这一发现有助于将 ES-Cu 用于铜缺乏症(如门克氏症)的治疗。意义声明:遗传性铜(Cu)缺乏症会导致致命的儿科疾病,如门克氏病,目前尚无有效的治疗方法。最近,有报道称一种铜转运化疗药物伊来克洛莫(ES)在门克氏症小鼠模型中具有治疗潜力。由于ES-Cu可能存在Cu诱导毒性的风险,因此确定其治疗指数至关重要。本文测定了缺铜疾病模型中 ES-Cu 的疗效和毒性生物标志物,以证明 ES-Cu 可以恢复铜酵素而不会引发毒性生物标志物。
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Elesclomol rescues mitochondrial copper deficiency in disease models without triggering cuproptosis.

Copper (Cu) is an essential cofactor for metalloenzymes such as cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial electron transport chain. Mutations that directly or indirectly prevent Cu transport to mitochondria result in lethal pediatric diseases, such as Menkes disease. There is no clinically approved treatment for Menkes disease. We recently discovered that an investigational chemotherapy drug, elesclomol (ES), when complexed with Cu (ES-Cu), rescues mitochondrial Cu deficiency, activates CcO, and prevents perinatal lethality in a mouse model of Menkes disease. However, ES-Cu also has the potential to trigger cuproptosis, a type of Cu-dependent cell death. Therefore, to develop ES-Cu as a therapeutic agent for Menkes disease, it is critical to determine the therapeutic index of ES-Cu in Cu-deficient models. To this end, we used a Cu-deficient rat cardiomyocyte cell line and a mottled-brindled mouse model of severe Menkes disease to determine the toxicity and efficacy of ES-Cu. Our cell culture studies demonstrated that the EC50 of ES-Cu is ∼50-fold lower than IC50. Moreover, the biomarkers of Cu toxicity, including lipoylated proteins and a subset of iron-sulfur cluster-containing proteins of mitochondria, are activated only when ES-Cu is used at ∼10-fold to 25-fold higher than its EC50. Importantly, none of these biomarkers are activated in mottled-brindled mice treated with therapeutic doses of ES-Cu. Our study shows that ES-Cu can deliver Cu to CcO both in vitro and in vivo without triggering cuproptosis, a finding that could facilitate its use in Cu deficiency disorders, such as Menkes disease. SIGNIFICANCE STATEMENT: Genetic copper (Cu) deficiency causes lethal pediatric diseases, such as Menkes disease, which lacks approved treatment. Recently, the therapeutic potential of elesclomol (ES), a Cu-transporting chemotherapeutic drug, in a mouse model of Menkes disease has been reported. Because of the potential risk of Cu-induced toxicity from ES-Cu, it is crucial to determine its therapeutic index. Here, the biomarkers of ES-Cu efficacy and toxicity in Cu-deficient disease models were measured to demonstrate that ES-Cu can restore cuproenzymes without triggering toxicity biomarkers.

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来源期刊
CiteScore
6.90
自引率
0.00%
发文量
115
审稿时长
1 months
期刊介绍: A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.
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