Brogyányi Tereza, Kaplánek Robert, Kejík Zdeněk, Hosnedlová Božena, Antonyová Veronika, Abramenko Nikita, Veselá Kateřina, Martásek Pavel, Vokurka Martin, Richardson Des R, Jakubek Milan
BIOCEV, First Faculty of Medicine, Charles University, Prague, Průmyslová 595, 252 50 Vestec, Czech Republic; Institute of Pathological Physiology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 5, 128 53 Prague, Czech Republic.
BIOCEV, First Faculty of Medicine, Charles University, Prague, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00 Prague, Czech Republic.
Biomed Pharmacother. 2022 Nov;155:113736. doi: 10.1016/j.biopha.2022.113736. Epub 2022 Sep 23.
Dysregulation of iron homeostasis is one of the important processes in the development of many oncological diseases, such as pancreatic cancer. Targeting it with specific agents, such as an iron chelator, are promising therapeutic methods. In this study, we tested the cytotoxicity of novel azulene hydrazide-hydrazone-based chelators against pancreatic cancer cell lines (MIA PaCa-2, PANC-1, AsPC-1). All prepared chelators (compounds 4-6) showed strong cytotoxicity against pancreatic cancer cell lines and high selectivity for cancer cell lines compared to the healthy line. Their cytotoxicity is lower than thiosemicarbazone-based chelators Dp44mT and DpC, but significantly higher than hydroxamic acid-based chelator DFO. The chelator tested showed mitochondrial and lysosomal co-localization and its mechanism of action was based on the induction of hypoxia-inducible factor-1-alpha (HIF-1α), N-myc downstream-regulated gene-1 (NDRG1) and transferrin receptor 1 (TfR1). This strongly implies that the cytotoxic effect of tested chelators could be associated with mitophagy induction. Lipinski's rule of five analyses was performed to determine whether the prepared compounds had properties ensuring their bioavailability. In addition, the drug-likeness and drug-score were calculated and discussed.
铁稳态失调是许多肿瘤疾病（如胰腺癌）发展过程中的重要进程之一。用特定药物（如铁螯合剂）靶向治疗是很有前景的治疗方法。在本研究中，我们测试了新型基于薁酰肼腙的螯合剂对胰腺癌细胞系（MIA PaCa-2、PANC-1、AsPC-1）的细胞毒性。所有制备的螯合剂（化合物4 - 6）对胰腺癌细胞系均表现出强烈的细胞毒性，且与健康细胞系相比，对癌细胞系具有高选择性。它们的细胞毒性低于基于硫代氨基脲的螯合剂Dp44mT和DpC，但显著高于基于异羟肟酸的螯合剂DFO。所测试的螯合剂显示出线粒体和溶酶体共定位，其作用机制基于缺氧诱导因子-1-α（HIF-1α）、N - myc下游调控基因-1（NDRG1）和转铁蛋白受体1（TfR1）的诱导。这强烈表明所测试螯合剂的细胞毒性可能与线粒体自噬诱导有关。进行了Lipinski五规则分析，以确定所制备的化合物是否具有确保其生物利用度的性质。此外，还计算并讨论了类药性和药物评分。
