PloS one, 2012-10, Vol.7 (10), p.e48175
2012
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- Autor(en) / Beteiligte
- Titel
- Susceptibility of human head and neck cancer cells to combined inhibition of glutathione and thioredoxin metabolism
- Ist Teil von
- PloS one, 2012-10, Vol.7 (10), p.e48175
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Increased glutathione (GSH) and thioredoxin (Trx) metabolism are mechanisms that are widely implicated in resistance of cancer cells to chemotherapy. The current study determined if simultaneous inhibition of GSH and Trx metabolism enhanced cell killing of human head and neck squamous cell carcinoma (HNSCC) cells by a mechanism involving oxidative stress. Inhibition of GSH and Trx metabolism with buthionine sulfoximine (BSO) and auranofin (AUR), respectively, induced significant decreases in clonogenic survival compared to either drug alone in FaDu, Cal-27 and SCC-25 HNSCC cells in vitro and in vivo in Cal-27 xenografts. BSO+AUR significantly increased glutathione and thioredoxin oxidation and suppressed peroxiredoxin activity in vitro. Pre-treatment with N-acetylcysteine completely reversed BSO+AUR-induced cell killing in FaDu and Cal-27 cells, while catalase and selenium supplementation only inhibited BSO+AUR-induced cell killing in FaDu cells. BSO+AUR decreased caspase 3/7 activity in HNSCC cells and significantly reduced the viability of both Bax/Bak double knockout (DKO) and DKO-Bax reconstituted hematopoietic cells suggesting that necrosis was involved. BSO+AUR also significantly sensitized FaDu, Cal-27, SCC-25 and SQ20B cells to cell killing induced by the EGFR inhibitor Erlotinib in vitro. These results support the conclusion that simultaneous inhibition of GSH and Trx metabolism pathways induces oxidative stress and clonogenic killing in HNSCCs and this strategy may be useful in sensitizing HNSCCs to EGFR inhibitors.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0048175Titel-ID: cdi_plos_journals_1326561471
- Format
- –
- Schlagworte
- Acetylcysteine, Animals, Antineoplastic Combined Chemotherapy Protocols - pharmacology, Antineoplastic Combined Chemotherapy Protocols - therapeutic use, Apoptosis, Auranofin - administration & dosage, Biology, Buthionine sulfoximine, Buthionine Sulfoximine - administration & dosage, Cancer, Cancer cells, Cancer prevention, Cancer research, Cancer therapies, Carcinoma, Squamous Cell - drug therapy, Caspase, Caspase-3, Catalase, Catalase - metabolism, Cell Line, Tumor, Cell Survival - drug effects, Chemotherapy, Disease susceptibility, Drug Synergism, Epidermal growth factor, Epidermal growth factor receptors, Erlotinib Hydrochloride, Female, Free radicals, Gene Knockdown Techniques, Glutathione, Glutathione - biosynthesis, Glutathione Peroxidase - metabolism, Glutathione Reductase - metabolism, Head, Head & neck cancer, Head and neck cancer, Head and Neck Neoplasms - drug therapy, Humans, Inhibition, Interdisciplinary aspects, Medicine, Metabolism, Mice, Mice, Nude, Necrosis, Oncology, Oncology, Experimental, Oxidation, Oxidation-Reduction, Oxidative metabolism, Oxidative Stress, Pathology, Peroxiredoxin, Peroxiredoxins - metabolism, Physiological aspects, Prevention, Quinazolines - administration & dosage, RNA, Small Interfering - genetics, Rodents, Selenium, Sensitizing, Sodium, Squamous cell carcinoma, Supplements, Thiols, Thioredoxin, Thioredoxin-Disulfide Reductase - genetics, Thioredoxin-Disulfide Reductase - metabolism, Thioredoxins, Thioredoxins - biosynthesis, Toxicology, Viability, Xenograft Model Antitumor Assays, Xenografts