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

Arya Sobhakumari; Laurie Love-Homan; Elise V M Fletcher; Sean M Martin; Arlene D Parsons; Douglas R Spitz; C Michael Knudson; Andrean L Simons

doi:10.1371/journal.pone.0048175

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

Journal article

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

Arya Sobhakumari, Laurie Love-Homan, Elise V M Fletcher, Sean M Martin, Arlene D Parsons, Douglas R Spitz, C Michael Knudson and Andrean L Simons

PloS one, Vol.7(10), pp.e48175-e48175

2012

DOI: 10.1371/journal.pone.0048175

PMCID: PMC3485193

PMID: 23118946

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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.

Erlotinib Hydrochloride

RNA, Small Interfering - genetics

Oxidative Stress

Thioredoxin-Disulfide Reductase - genetics

Glutathione Reductase - metabolism

Humans

Peroxiredoxins - metabolism

Antineoplastic Combined Chemotherapy Protocols - pharmacology

Gene Knockdown Techniques

Necrosis

Glutathione - biosynthesis

Thioredoxins - biosynthesis

Auranofin - administration & dosage

Thioredoxin-Disulfide Reductase - metabolism

Female

Quinazolines - administration & dosage

Cell Survival - drug effects

Glutathione Peroxidase - metabolism

Oxidation-Reduction

Head and Neck Neoplasms - drug therapy

Catalase - metabolism

Drug Synergism

Xenograft Model Antitumor Assays

Animals

Buthionine Sulfoximine - administration & dosage

Carcinoma, Squamous Cell - drug therapy

Antineoplastic Combined Chemotherapy Protocols - therapeutic use

Mice, Nude

Cell Line, Tumor

Mice

Details

Title: Subtitle: Susceptibility of human head and neck cancer cells to combined inhibition of glutathione and thioredoxin metabolism
Creators: Arya Sobhakumari - Department of Pathology, The University of Iowa, Iowa City, Iowa, USA
Laurie Love-Homan
Elise V M Fletcher
Sean M Martin
Arlene D Parsons
Douglas R Spitz
C Michael Knudson
Andrean L Simons
Resource Type: Journal article
Publication Details: PloS one, Vol.7(10), pp.e48175-e48175
DOI: 10.1371/journal.pone.0048175
PMID: 23118946
PMCID: PMC3485193
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: K01CA134941 / NCI NIH HHS T32 CA078586 / NCI NIH HHS R01CA133114 / NCI NIH HHS K01 CA134941 / NCI NIH HHS P30CA086862 / NCI NIH HHS R01 CA133114 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 2012
Academic Unit: Oral Pathology, Radiology and Medicine; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology
Record Identifier: 9984047668902771

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