ORIGINAL RESEARCH article
Front. Oncol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1580828
This article is part of the Research TopicCombination Therapies in Cancer Treatment: Enhancing Efficacy and Reducing ResistanceView all 11 articles
Iodine-131 Induces Ferroptosis and Synergizes with Sulfasalazine in Differentiated Thyroid Cancer Cells via Suppressing SLC7A11
Provisionally accepted
- 1Guangzhou University of Chinese Medicine, Guangzhou, China
- 2Department of Nuclear Medicine, General Hospital of Southern Theatre Command of PLA, Guangzhou, China
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Iodine-131 ( 131 I) plays a key role in the treatment of differentiated thyroid cancer (DTC). Ferroptosis represents a form of regulated cell death that is distinct from necrosis and apoptosis, constituting a unique mode of programmed cell death. In this study, we aimed to ascertain the potential of 131 I to trigger ferroptosis in DTC and to assess the synergistic therapeutic impact of combining 131 I with sulfasalazine (SAS), a ferroptosis inducer, in the context of DTC. The FTC-133 and TPC-1 cell lines were employed to evaluate the impact of 131 I and SAS on cellular functions. Ferrostatin-1 (Fer-1) reversed the cell viability and colony formation ability inhibited by 131 I. 131 I led to an elevation in the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and lipid peroxidation. DTC cells exposed to 131 I displayed characteristic ferroptotic ultrastructure, featuring shrunken mitochondria with increased membrane density. Concurrently, there was a reduction in the content of glutathione (GSH), as well as a downregulation of the expression levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) in the cells treated with 131 I. The CI values for the combination of SAS and 131 I in DTC cells were less than 1, demonstrating that SAS synergized with 131 I. Moreover, the combination of SAS and 131 I significantly increased the MDA levels and lipid peroxidation, decreased the GSH levels, and suppressed the expression of SLC7A11 and GPX4, while SLC7A11 knockdown significantly enhanced ferroptosis-related markers in DTC cells. Animal experiments demonstrated that SAS synergized with 131 I resulted in notable decreases in tumor volume and weight. Furthermore, immunohistochemical analyses revealed that the combination of 131 I and SAS significantly downregulated the expression of GPX4 and SLC7A11 in vivo. Taken together, our results suggest that 131 I may induce lipid peroxidation and ferroptosis, and demonstrate the potential for a synergistic therapeutic effect when 131 I is combined with SAS in the treatment of DTC.
Keywords: Differentiated thyroid cancer, ferroptosis, Iodine-131, Sulfasalazine, SLC7A11 (xCT)
Received: 21 Feb 2025; Accepted: 23 Apr 2025.
Copyright: © 2025 Ling, Zhang, Zhang, Wang, Ma and Yin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: JH Zhang, Department of Nuclear Medicine, General Hospital of Southern Theatre Command of PLA, Guangzhou, China
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