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Susceptibility of human head and neck cancer cells to combined inhibition of glutathione and thioredoxin metabolism.
PLoS One. 2012; 7(10):e48175.Plos

Abstract

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.

Authors+Show Affiliations

Department of Pathology, The University of Iowa, Iowa City, Iowa, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23118946

Citation

Sobhakumari, Arya, et al. "Susceptibility of Human Head and Neck Cancer Cells to Combined Inhibition of Glutathione and Thioredoxin Metabolism." PloS One, vol. 7, no. 10, 2012, pp. e48175.
Sobhakumari A, Love-Homan L, Fletcher EV, et al. Susceptibility of human head and neck cancer cells to combined inhibition of glutathione and thioredoxin metabolism. PLoS ONE. 2012;7(10):e48175.
Sobhakumari, A., Love-Homan, L., Fletcher, E. V., Martin, S. M., Parsons, A. D., Spitz, D. R., Knudson, C. M., & Simons, A. L. (2012). Susceptibility of human head and neck cancer cells to combined inhibition of glutathione and thioredoxin metabolism. PloS One, 7(10), e48175. https://doi.org/10.1371/journal.pone.0048175
Sobhakumari A, et al. Susceptibility of Human Head and Neck Cancer Cells to Combined Inhibition of Glutathione and Thioredoxin Metabolism. PLoS ONE. 2012;7(10):e48175. PubMed PMID: 23118946.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Susceptibility of human head and neck cancer cells to combined inhibition of glutathione and thioredoxin metabolism. AU - Sobhakumari,Arya, AU - Love-Homan,Laurie, AU - Fletcher,Elise V M, AU - Martin,Sean M, AU - Parsons,Arlene D, AU - Spitz,Douglas R, AU - Knudson,C Michael, AU - Simons,Andrean L, Y1 - 2012/10/31/ PY - 2012/06/19/received PY - 2012/09/21/accepted PY - 2012/11/3/entrez PY - 2012/11/3/pubmed PY - 2013/4/16/medline SP - e48175 EP - e48175 JF - PloS one JO - PLoS ONE VL - 7 IS - 10 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23118946/Susceptibility_of_human_head_and_neck_cancer_cells_to_combined_inhibition_of_glutathione_and_thioredoxin_metabolism_ L2 - http://dx.plos.org/10.1371/journal.pone.0048175 DB - PRIME DP - Unbound Medicine ER -