Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth
Thioredoxin Reductase (TrxR) functions to recycle thioredoxin (Trx) during hydroperoxide metabolism mediated by peroxiredoxins and is currently being targeted using the FDA-approved anti-rheumatic drug, auranofin (AF), to selectively sensitize cancer cells to therapy. AF treatment decreased TrxR act...
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| Format: | Article |
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Taylor & Francis Group
2024-12-01
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| Series: | Cancer Biology & Therapy |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15384047.2024.2382524 |
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| author | Spenser S. Johnson Dijie Liu Jordan T. Ewald Claudia Robles-Planells Casey Pulliam Keegan A. Christensen Khaliunaa Bayanbold Brian R. Wels Shane R. Solst M. Sue O’Dorisio Yusuf Menda Douglas R. Spitz Melissa A. Fath |
| author_facet | Spenser S. Johnson Dijie Liu Jordan T. Ewald Claudia Robles-Planells Casey Pulliam Keegan A. Christensen Khaliunaa Bayanbold Brian R. Wels Shane R. Solst M. Sue O’Dorisio Yusuf Menda Douglas R. Spitz Melissa A. Fath |
| author_sort | Spenser S. Johnson |
| collection | DOAJ |
| description | Thioredoxin Reductase (TrxR) functions to recycle thioredoxin (Trx) during hydroperoxide metabolism mediated by peroxiredoxins and is currently being targeted using the FDA-approved anti-rheumatic drug, auranofin (AF), to selectively sensitize cancer cells to therapy. AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the H727 atypical lung carcinoid cell line. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, an FDA-approved multi-kinase inhibitor that depleted intracellular glutathione (GSH). The pharmacokinetic, pharmacodynamic, and safety profile of AF was examined in nude mice with DMS273 xenografts administered AF intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1−5 d. Plasma levels of AF were 10–20 μM (determined by mass spectrometry of gold), and the optimal inhibition of TrxR activity was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. This AF treatment extended for 14 d, inhibited TrxR (>75%), and resulted in a significant prolongation of median overall survival from 19 to 23 d (p = .04, N = 30 controls, 28 AF). In this experiment, there were no observed changes in animal bodyweight, complete blood counts (CBCs), bone marrow toxicity, blood urea nitrogen, or creatinine. These results support the hypothesis that AF effectively inhibits TrxR both in vitro and in vivo in SCLC, sensitizes NETs and SCLC to sorafenib, and could be repurposed as an adjuvant therapy with targeted agents that induce disruptions in thiol metabolism. |
| format | Article |
| id | doaj-art-c5a3742216384e1498585e82c931ad1b |
| institution | Kabale University |
| issn | 1538-4047 1555-8576 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Cancer Biology & Therapy |
| spelling | doaj-art-c5a3742216384e1498585e82c931ad1b2024-12-13T06:53:24ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762024-12-0125110.1080/15384047.2024.2382524Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growthSpenser S. Johnson0Dijie Liu1Jordan T. Ewald2Claudia Robles-Planells3Casey Pulliam4Keegan A. Christensen5Khaliunaa Bayanbold6Brian R. Wels7Shane R. Solst8M. Sue O’Dorisio9Yusuf Menda10Douglas R. Spitz11Melissa A. Fath12Department of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USADepartment Pediatrics, University of Iowa Hospitals and Clinics, IA, USADepartment of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USADepartment Pediatrics, University of Iowa Hospitals and Clinics, IA, USADepartment of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USADepartment of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USADepartment of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USAState Hygienic Laboratory, University of Iowa, IA, USADepartment of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USADepartment Pediatrics, University of Iowa Hospitals and Clinics, IA, USADepartment of Radiology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, IA, USADepartment of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USADepartment of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USAThioredoxin Reductase (TrxR) functions to recycle thioredoxin (Trx) during hydroperoxide metabolism mediated by peroxiredoxins and is currently being targeted using the FDA-approved anti-rheumatic drug, auranofin (AF), to selectively sensitize cancer cells to therapy. AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the H727 atypical lung carcinoid cell line. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, an FDA-approved multi-kinase inhibitor that depleted intracellular glutathione (GSH). The pharmacokinetic, pharmacodynamic, and safety profile of AF was examined in nude mice with DMS273 xenografts administered AF intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1−5 d. Plasma levels of AF were 10–20 μM (determined by mass spectrometry of gold), and the optimal inhibition of TrxR activity was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. This AF treatment extended for 14 d, inhibited TrxR (>75%), and resulted in a significant prolongation of median overall survival from 19 to 23 d (p = .04, N = 30 controls, 28 AF). In this experiment, there were no observed changes in animal bodyweight, complete blood counts (CBCs), bone marrow toxicity, blood urea nitrogen, or creatinine. These results support the hypothesis that AF effectively inhibits TrxR both in vitro and in vivo in SCLC, sensitizes NETs and SCLC to sorafenib, and could be repurposed as an adjuvant therapy with targeted agents that induce disruptions in thiol metabolism.https://www.tandfonline.com/doi/10.1080/15384047.2024.2382524auranofinsorafenibsmall cell lung cancerthioredoxin reductaselung neuroendocrine tumordms273 |
| spellingShingle | Spenser S. Johnson Dijie Liu Jordan T. Ewald Claudia Robles-Planells Casey Pulliam Keegan A. Christensen Khaliunaa Bayanbold Brian R. Wels Shane R. Solst M. Sue O’Dorisio Yusuf Menda Douglas R. Spitz Melissa A. Fath Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth Cancer Biology & Therapy auranofin sorafenib small cell lung cancer thioredoxin reductase lung neuroendocrine tumor dms273 |
| title | Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth |
| title_full | Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth |
| title_fullStr | Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth |
| title_full_unstemmed | Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth |
| title_short | Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth |
| title_sort | auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells nets and small cell lung cancer sclc cells to sorafenib as well as inhibiting sclc xenograft growth |
| topic | auranofin sorafenib small cell lung cancer thioredoxin reductase lung neuroendocrine tumor dms273 |
| url | https://www.tandfonline.com/doi/10.1080/15384047.2024.2382524 |
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