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Targeting of the Glutathione, Thioredoxin, and Nrf2 Antioxidant Systems in Head and Neck Cancer.
Antioxid Redox Signal. 2017 07 10; 27(2):106-114.AR

Abstract

AIMS

The glutathione (GSH), thioredoxin (Trx), and Nrf2 systems represent a major defense against reactive oxygen species (ROS), the cellular imbalance of which in cancer promotes growth and therapeutic resistance. This study investigated whether targeting the GSH, Trx, and Nrf2 antioxidant systems effectively eliminated head and neck cancer (HNC).

RESULTS

At high concentrations, auranofin, but not buthionine sulfoximine (BSO) alone, decreased the viability of HNC, whereas even at low concentrations, auranofin plus BSO synergized to kill HNC cells. Dual silencing of the genes for GCLM and TrxR1 induced GSH depletion, Trx activity inhibition, and ROS accumulation, synergistically killing HNC cells. Inhibition of the GSH and Trx systems resulted in activation of the Nrf2-antioxidant response element (ARE) pathway, which may result in suboptimal GSH and Trx inhibition where HNC is resistant. Genetic inhibition of Nrf2 and/or HO-1 or trigonelline enhanced growth suppression, ROS accumulation, and cell death from GSH and Trx inhibition. The in vivo effects of GSH, Trx, and Nrf2 system inhibition were confirmed in a mouse HNC xenograft model by achieving growth inhibition >60% compared with those of control. Innovations: This study is the first to show that triple inhibition of GSH, Trx, and Nrf2 pathways could be an effective method to overcome the resistance of HNC.

CONCLUSIONS

Inhibition of the Nrf2-ARE pathway in addition to dual inhibition of the GSH and Trx antioxidant systems can effectively eliminate resistant HNC. Antioxid. Redox Signal. 27, 106-114.

Authors+Show Affiliations

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Republic of Korea.Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Republic of Korea.Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Republic of Korea.Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Republic of Korea.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27733046

Citation

Roh, Jong-Lyel, et al. "Targeting of the Glutathione, Thioredoxin, and Nrf2 Antioxidant Systems in Head and Neck Cancer." Antioxidants & Redox Signaling, vol. 27, no. 2, 2017, pp. 106-114.
Roh JL, Jang H, Kim EH, et al. Targeting of the Glutathione, Thioredoxin, and Nrf2 Antioxidant Systems in Head and Neck Cancer. Antioxid Redox Signal. 2017;27(2):106-114.
Roh, J. L., Jang, H., Kim, E. H., & Shin, D. (2017). Targeting of the Glutathione, Thioredoxin, and Nrf2 Antioxidant Systems in Head and Neck Cancer. Antioxidants & Redox Signaling, 27(2), 106-114. https://doi.org/10.1089/ars.2016.6841
Roh JL, et al. Targeting of the Glutathione, Thioredoxin, and Nrf2 Antioxidant Systems in Head and Neck Cancer. Antioxid Redox Signal. 2017 07 10;27(2):106-114. PubMed PMID: 27733046.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting of the Glutathione, Thioredoxin, and Nrf2 Antioxidant Systems in Head and Neck Cancer. AU - Roh,Jong-Lyel, AU - Jang,Hyejin, AU - Kim,Eun Hye, AU - Shin,Daiha, Y1 - 2016/11/14/ PY - 2016/10/14/pubmed PY - 2018/3/1/medline PY - 2016/10/14/entrez KW - Nrf2 KW - glutathione KW - head and neck cancer KW - reactive oxygen species KW - thioredoxin SP - 106 EP - 114 JF - Antioxidants & redox signaling JO - Antioxid. Redox Signal. VL - 27 IS - 2 N2 - AIMS: The glutathione (GSH), thioredoxin (Trx), and Nrf2 systems represent a major defense against reactive oxygen species (ROS), the cellular imbalance of which in cancer promotes growth and therapeutic resistance. This study investigated whether targeting the GSH, Trx, and Nrf2 antioxidant systems effectively eliminated head and neck cancer (HNC). RESULTS: At high concentrations, auranofin, but not buthionine sulfoximine (BSO) alone, decreased the viability of HNC, whereas even at low concentrations, auranofin plus BSO synergized to kill HNC cells. Dual silencing of the genes for GCLM and TrxR1 induced GSH depletion, Trx activity inhibition, and ROS accumulation, synergistically killing HNC cells. Inhibition of the GSH and Trx systems resulted in activation of the Nrf2-antioxidant response element (ARE) pathway, which may result in suboptimal GSH and Trx inhibition where HNC is resistant. Genetic inhibition of Nrf2 and/or HO-1 or trigonelline enhanced growth suppression, ROS accumulation, and cell death from GSH and Trx inhibition. The in vivo effects of GSH, Trx, and Nrf2 system inhibition were confirmed in a mouse HNC xenograft model by achieving growth inhibition >60% compared with those of control. Innovations: This study is the first to show that triple inhibition of GSH, Trx, and Nrf2 pathways could be an effective method to overcome the resistance of HNC. CONCLUSIONS: Inhibition of the Nrf2-ARE pathway in addition to dual inhibition of the GSH and Trx antioxidant systems can effectively eliminate resistant HNC. Antioxid. Redox Signal. 27, 106-114. SN - 1557-7716 UR - https://www.unboundmedicine.com/medline/citation/27733046/Targeting_of_the_Glutathione_Thioredoxin_and_Nrf2_Antioxidant_Systems_in_Head_and_Neck_Cancer_ L2 - https://www.liebertpub.com/doi/full/10.1089/ars.2016.6841?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -