Institut Parisien de Chimie Moléculaire, Sorbonne Université, CNRS, UMR CNRS 8232, 4 Place Jussieu, F-75005 Paris, France.
Institut du Cerveau-Paris Brain Institute-ICM, Inserm, Sorbonne Université, CNRS, APHP, Hôpital de la Pitié Salpêtrière, F-75013 Paris, France.
Int J Mol Sci. 2021 Sep 27;22(19):10404. doi: 10.3390/ijms221910404.
Glioblastoma (GBM) is the most frequent and deadliest primary brain cancer in adults, justifying the search for new treatments. Some members of the iron-based ferrocifen family have demonstrated a high cytotoxic effect on various cancer cell lines via innovative mechanisms of action. Here, we evaluated the antiproliferative activity by wst-1 assay of six ferrocifens in 15 molecularly diverse GBM patient-derived cell lines (PDCLs). In five out of six compounds, the half maximal inhibitory concentration (IC) values varied significantly (10 nM < IC < 29.8 µM) while the remaining one (the tamoxifen-like complex) was highly cytotoxic against all PDCLs (mean IC = 1.28 µM). The pattern of response was comparable for the four ferrocifens bearing at least one phenol group and differed widely from those of the tamoxifen-like complex and the complex with no phenol group. An RNA sequencing differential analysis showed that response to the diphenol ferrocifen relied on the activation of the Death Receptor signaling pathway and the modulation of FAS expression. Response to this complex was greater in PDCLs from the Mesenchymal or Proneural transcriptomic subtypes compared to the ones from the Classical subtype. These results provide new information on the mechanisms of action of ferrocifens and highlight a broader diversity of behavior than previously suspected among members of this family. They also support the case for a molecular-based personalized approach to future use of ferrocifens in the treatment of GBM.
胶质母细胞瘤（GBM）是成人中最常见和最致命的原发性脑癌，因此有必要寻找新的治疗方法。铁基 Ferrocifen 家族的一些成员通过创新的作用机制对各种癌细胞系表现出高细胞毒性作用。在这里，我们通过 wst-1 测定法评估了六种 Ferrocifen 在 15 种分子多样化的胶质母细胞瘤患者来源细胞系（PDCL）中的增殖活性。在六种化合物中有五种，半最大抑制浓度（IC）值差异显著（10 nM < IC < 29.8 µM），而其余一种（类似他莫昔芬的复合物）对所有 PDCL 均具有高度细胞毒性（平均 IC = 1.28 µM）。对至少含有一个酚基团的四种 Ferrocifen 的反应模式相似，与类似他莫昔芬的复合物和没有酚基团的复合物的反应模式有很大不同。RNA 测序差异分析表明，二酚 Ferrocifen 的反应依赖于死亡受体信号通路的激活和 FAS 表达的调节。与经典转录组亚型相比，在间充质或神经前转录组亚型的 PDCL 中，对该复合物的反应更大。这些结果提供了关于 Ferrocifen 作用机制的新信息，并强调了该家族成员之间比以前怀疑的更广泛的行为多样性。它们还支持在未来使用 Ferrocifen 治疗 GBM 时采用基于分子的个性化方法。
