A novel iron(II) phenanthroline complex exhibits anticancer activity against TFR1-overexpressing esophageal squamous cell carcinoma cells through ROS accumulation and DNA damage
| Autor: | Chan Liu, Xueyun Zhong, Jianxian Huang, Jiecheng Ye, Lihui Wang, Jiwei Ma |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell cycle checkpoint Esophageal Neoplasms DNA damage Thioredoxin reductase Transferrin receptor Antineoplastic Agents Endocytosis Biochemistry 03 medical and health sciences 0302 clinical medicine Antigens CD Receptors Transferrin medicine Humans Pharmacology chemistry.chemical_classification Cisplatin Reactive oxygen species Dose-Response Relationship Drug Gene Expression Regulation Neoplastic 030104 developmental biology chemistry Apoptosis 030220 oncology & carcinogenesis Cancer research Esophageal Squamous Cell Carcinoma Reactive Oxygen Species Iron Compounds medicine.drug DNA Damage Phenanthrolines |
| Zdroj: | Biochemical pharmacology. 166 |
| ISSN: | 1873-2968 |
| Popis: | Esophageal squamous cell carcinoma (ESCC) is one of the most common and aggressive cancers worldwide, especially in China, with poor prognosis due to the lack of effective therapeutic strategies. Here, the anticancer effect and pharmacological mechanism of a newly synthesized Fe(II) phenanthroline complex was studied in ESCC. Our data showed that transferrin receptor 1 (TFR1) was specifically overexpressed in ESCC tissues compared to its expression in normal esophageal tissues, a finding further supported by public datasets. The newly synthesized Fe(II) complex was selectively transported into ESCC cells overexpressing TFR1 through TFR1-mediated endocytosis and exhibited anticancer activity in a dose-dependent manner. The mechanistic study elucidated that the Fe(II) complex caused cell cycle arrest at the G0/G1 phase by blocking the CDK4/6-cyclin D1 complex and induced mitochondria-mediated apoptosis. Furthermore, exposure to the Fe(II) complex led to excessive reactive oxygen species (ROS) accumulation by thioredoxin reductase (TrxR) inhibition and DNA double-strand breaks (DSBs), which in turn sequentially activated ATM, CHK1/2 and p53. Moreover, combination treatment with cisplatin and the Fe(II) complex exhibited a synergistic effect in ESCC cells. Taken together, our results initially suggest the potential application of the Fe(II) complex in ESCC chemotherapy, especially for patients with TFR1 overexpression. |
| Databáze: | OpenAIRE |
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