Bernkop-Schnürch Astrid Dagmar, Hermann Martin, Leitner Daniel, Talasz Heribert, Descher Hubert Aaron, Hohloch Stephan, Gust Ronald, Kircher Brigitte
Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI-Center for Molecular Biosciences Innsbruck, CCB-Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria.
ACS Omega. 2024 Aug 5;9(33):35394-35407. doi: 10.1021/acsomega.4c01314. eCollection 2024 Aug 20.
Fluorinated chlorido[salophene]iron(III) complexes (salophene = ,'-bis(salicylidene)-1,2-phenylenediamine) are promising anticancer agents. Apoptosis and necrosis induction have already been described as part of their mode of action. However, the involvement of ferroptosis in cell death induction, as confirmed for other chlorido[salophene]iron(III) complexes, has not yet been investigated. Furthermore, the mechanism of cellular uptake of these compounds is unknown. Therefore, the biological activity of the fluorescent chlorido[salophene]iron(III) complexes with a fluorine substituent at positions 3, 4, 5, or 6 at the salicylidene moieties (-) was evaluated in malignant and nonmalignant cell lines with focus on the involvement of the transferrin receptor-1 (TfR-1) in cellular uptake, the influence of the complexes on mitochondrial function, and the analysis of the molecular mechanism of cell death. All complexes significantly decreased the metabolic activity in the tested ovarian cancer (A2780, A2780cis), breast cancer (MDA-MB 231), and leukemia (HL-60) cell lines, while the nonmalignant human stroma cell line HS-5 at a concentration of 0.5 μM, which represents the IC of the complexes in most of the used tumorigenic cell lines, was not affected. The mitochondrial function was impaired, as evidenced by a reduced mitochondrial membrane potential ΔΨm and decreased mitochondrial activity. Besides apoptosis and necroptosis, ferroptosis was identified as part of the mode of action. It was further demonstrated for the first time that fluorinated chlorido[salophene]iron(III) complexes downregulate TfR-1 expression, comparable to ferristatin II, an iron transport inhibitor that acts via TfR-1 degradation. FerroOrange staining further indicated that the complexes strongly increased the intracellular iron(II) level as a driving force to induce ferroptosis. In conclusion, these fluorinated chlorido[salophene]iron(III) complexes are potent, tumor cell-specific chemotherapeutic agents, with the potential to treat various types of cancers.
氟化氯代[水杨醛缩邻苯二胺]铁(III)配合物（水杨醛缩邻苯二胺 = ，'-双（水杨基亚甲基）-1,2-苯二胺）是很有前景的抗癌剂。凋亡和坏死诱导已被描述为其作用方式的一部分。然而，正如其他氯代[水杨醛缩邻苯二胺]铁(III)配合物所证实的那样，铁死亡在细胞死亡诱导中的参与尚未得到研究。此外，这些化合物的细胞摄取机制尚不清楚。因此，对水杨基亚甲基部分（-）的3、4、5或6位带有氟取代基的荧光氯代[水杨醛缩邻苯二胺]铁(III)配合物的生物活性进行了评估，重点研究转铁蛋白受体-1（TfR-1）在细胞摄取中的作用、配合物对线粒体功能的影响以及细胞死亡分子机制的分析。所有配合物均显著降低了所测试的卵巢癌（A2780、A2780cis）、乳腺癌（MDA-MB 231）和白血病（HL-60）细胞系中的代谢活性，而浓度为0.5 μM的非恶性人基质细胞系HS-5未受影响，该浓度代表了大多数所用致瘤细胞系中配合物的半数抑制浓度。线粒体功能受损，表现为线粒体膜电位ΔΨm降低和线粒体活性下降。除了凋亡和坏死性凋亡外，铁死亡也被确定为作用方式的一部分。首次进一步证明，氟化氯代[水杨醛缩邻苯二胺]铁(III)配合物下调TfR-1表达，与通过TfR-1降解起作用的铁转运抑制剂铁抑素II相当。FerroOrange染色进一步表明，配合物强烈提高细胞内铁(II)水平，作为诱导铁死亡的驱动力。总之，这些氟化氯代[水杨醛缩邻苯二胺]铁(III)配合物是有效的、肿瘤细胞特异性的化疗药物，具有治疗多种类型癌症的潜力。
