Alov Petko, Al Sharif Merilin, Aluani Denitsa, Chegaev Konstantin, Dinic Jelena, Divac Rankov Aleksandra, Fernandes Miguel X, Fusi Fabio, García-Sosa Alfonso T, Juvonen Risto, Kondeva-Burdina Magdalena, Padrón José M, Pajeva Ilza, Pencheva Tania, Puerta Adrián, Raunio Hannu, Riganti Chiara, Tsakovska Ivanka, Tzankova Virginia, Yordanov Yordan, Saponara Simona
Department of QSAR and Molecular Modelling, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria.
Front Pharmacol. 2022 Mar 7;13:831791. doi: 10.3389/fphar.2022.831791. eCollection 2022.
Sdox is a hydrogen sulfide (HS)-releasing doxorubicin effective in P-glycoprotein-overexpressing/doxorubicin-resistant tumor models and not cytotoxic, as the parental drug, in H9c2 cardiomyocytes. The aim of this study was the assessment of Sdox drug-like features and its absorption, distribution, metabolism, and excretion (ADME)/toxicity properties, by a multi- and transdisciplinary , , and approach. Doxorubicin was used as the reference compound. The profiling suggested that Sdox possesses higher lipophilicity and lower solubility compared to doxorubicin, and the off-targets prediction revealed relevant differences between Dox and Sdox towards several cancer targets, suggesting different toxicological profiles. data showed that Sdox is a substrate with lower affinity for P-glycoprotein, less hepatotoxic, and causes less oxidative damage than doxorubicin. Both anthracyclines inhibited CYP3A4, but not hERG currents. Unlike doxorubicin, the percentage of zebrafish live embryos at 72 hpf was not affected by Sdox treatment. In conclusion, these findings demonstrate that Sdox displays a more favorable drug-like ADME/toxicity profile than doxorubicin, different selectivity towards cancer targets, along with a greater preclinical efficacy in resistant tumors. Therefore, Sdox represents a prototype of innovative anthracyclines, worthy of further investigations in clinical settings.
Sdox是一种可释放硫化氢（HS）的阿霉素，在过表达P-糖蛋白/阿霉素耐药的肿瘤模型中有效，并且作为母体药物，对H9c2心肌细胞无细胞毒性。本研究的目的是通过多学科和跨学科的方法评估Sdox的类药物特性及其吸收、分布、代谢和排泄（ADME）/毒性特性。阿霉素用作参考化合物。特性分析表明，与阿霉素相比，Sdox具有更高的亲脂性和更低的溶解度，脱靶预测揭示了阿霉素和Sdox在几个癌症靶点上的相关差异，表明它们具有不同的毒理学特征。ADME数据表明，Sdox是一种对P-糖蛋白亲和力较低的底物，肝毒性较小，比阿霉素引起的氧化损伤更少。两种蒽环类药物均抑制CYP3A4，但不抑制hERG电流。与阿霉素不同，Sdox处理对72 hpf时斑马鱼活胚胎的百分比没有影响。总之，这些发现表明，Sdox显示出比阿霉素更有利的类药物ADME/毒性特征，对癌症靶点具有不同的选择性，并且在耐药肿瘤中具有更高的临床前疗效。因此，Sdox代表了一种创新蒽环类药物的原型，值得在临床环境中进一步研究。
