دورية أكاديمية
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.
| العنوان: | 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. |
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| المؤلفون: | Johnson SS; Department of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USA., Liu D; Department Pediatrics, University of Iowa Hospitals and Clinics, IA, USA., Ewald JT; Department of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USA., Robles-Planells C; Department Pediatrics, University of Iowa Hospitals and Clinics, IA, USA., Pulliam C; Department of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USA., Christensen KA; Department of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USA., Bayanbold K; Department of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USA., Wels BR; State Hygienic Laboratory, University of Iowa, IA, USA., Solst SR; Department of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USA., O'Dorisio MS; Department Pediatrics, University of Iowa Hospitals and Clinics, IA, USA., Menda Y; Department of Radiology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, IA, USA., Spitz DR; Department of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USA., Fath MA; Department of Radiation Oncology, Holden Comprehensive Cancer Center, Free Radical and Radiation Biology Program, University of Iowa Hospitals and Clinics, IA, USA. |
| المصدر: | Cancer biology & therapy [Cancer Biol Ther] 2024 Dec 31; Vol. 25 (1), pp. 2382524. Date of Electronic Publication: 2024 Jul 25. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101137842 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1555-8576 (Electronic) Linking ISSN: 15384047 NLM ISO Abbreviation: Cancer Biol Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2015- : Philadelphia, PA : Taylor & Francis Original Publication: Georgetown, TX : Landes Bioscience, c2002- |
| مواضيع طبية MeSH: | Auranofin*/pharmacology , Auranofin*/therapeutic use , Sorafenib*/pharmacology , Sorafenib*/therapeutic use , Thioredoxin-Disulfide Reductase*/antagonists & inhibitors , Thioredoxin-Disulfide Reductase*/metabolism , Lung Neoplasms*/drug therapy , Lung Neoplasms*/pathology , Lung Neoplasms*/metabolism , Small Cell Lung Carcinoma*/drug therapy , Small Cell Lung Carcinoma*/pathology , Small Cell Lung Carcinoma*/metabolism , Xenograft Model Antitumor Assays* , Phenylurea Compounds*/pharmacology , Phenylurea Compounds*/therapeutic use, Animals ; Humans ; Mice ; Cell Line, Tumor ; Neuroendocrine Tumors/drug therapy ; Neuroendocrine Tumors/pathology ; Neuroendocrine Tumors/metabolism ; Mice, Nude ; Niacinamide/analogs & derivatives ; Niacinamide/pharmacology ; Niacinamide/therapeutic use ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use |
| مستخلص: | 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. |
| التعليقات: | Update of: bioRxiv. 2024 Jan 30:2023.05.07.539772. doi: 10.1101/2023.05.07.539772. (PMID: 37215042) |
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| معلومات مُعتمدة: | P01 CA217797 United States CA NCI NIH HHS; P30 CA086862 United States CA NCI NIH HHS; P01 CA244091 United States CA NCI NIH HHS; R50 CA243693 United States CA NCI NIH HHS; P50 CA174521 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: auranofin; dms273; glutathione; h727; lung neuroendocrine tumor; small cell lung cancer; sorafenib; thioredoxin reductase |
| المشرفين على المادة: | 3H04W2810V (Auranofin) 9ZOQ3TZI87 (Sorafenib) EC 1.8.1.9 (Thioredoxin-Disulfide Reductase) 0 (Phenylurea Compounds) 25X51I8RD4 (Niacinamide) 0 (Antineoplastic Agents) |
| تواريخ الأحداث: | Date Created: 20240725 Date Completed: 20240726 Latest Revision: 20240730 |
| رمز التحديث: | 20240730 |
| مُعرف محوري في PubMed: | PMC11275529 |
| DOI: | 10.1080/15384047.2024.2382524 |
| PMID: | 39054566 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1555-8576 |
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| DOI: | 10.1080/15384047.2024.2382524 |