Susceptibility of human head and neck cancer cells to combined inhibition of glutathione and thioredoxin metabolism

Autor: C. Michael Knudson, Arya Sobhakumari, Elise V.M. Fletcher, Douglas R. Spitz, Andrean L. Simons, Laurie Love-Homan, Sean M. Martin, Arlene D. Parsons
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Cancer Treatment
lcsh:Medicine
Oxidative Damage
Mice
chemistry.chemical_compound
Thioredoxins
0302 clinical medicine
Oral Diseases
Molecular Cell Biology
Basic Cancer Research
Antineoplastic Combined Chemotherapy Protocols
RNA
Small Interfering
lcsh:Science
Cellular Stress Responses
0303 health sciences
Multidisciplinary
Cell Death
Drug Synergism
Catalase
Glutathione
3. Good health
Glutathione Reductase
Cell killing
Oncology
Head and Neck Neoplasms
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Carcinoma
Squamous Cell
Medicine
Oncology Agents
Female
Thioredoxin
Oxidation-Reduction
Research Article
Thioredoxin-Disulfide Reductase
Cell Survival
Oral Medicine
Mice
Nude
Biology
Cell Growth
Erlotinib Hydrochloride
Necrosis
03 medical and health sciences
Auranofin
Cell Line
Tumor
Animals
Humans
Buthionine sulfoximine
Clonogenic assay
Buthionine Sulfoximine
030304 developmental biology
Glutathione Peroxidase
Peroxiredoxin activity
lcsh:R
Peroxiredoxins
Xenograft Model Antitumor Assays
Molecular biology
Oxidative Stress
stomatognathic diseases
chemistry
Apoptosis
Cancer cell
Quinazolines
lcsh:Q
Zdroj: PLoS ONE, Vol 7, Iss 10, p e48175 (2012)
PLoS ONE
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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