Inhibition of Glutathione and Thioredoxin Metabolism Enhances Sensitivity to Perifosine in Head and Neck Cancer Cells

Andrean L Simons; Arlene D Parsons; Katherine A Foster; Kevin P Orcutt; Melissa A Fath; Douglas R Spitz

doi:10.1155/2009/519563

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Inhibition of Glutathione and Thioredoxin Metabolism Enhances Sensitivity to Perifosine in Head and Neck Cancer Cells

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Inhibition of Glutathione and Thioredoxin Metabolism Enhances Sensitivity to Perifosine in Head and Neck Cancer Cells

Andrean L Simons, Arlene D Parsons, Katherine A Foster, Kevin P Orcutt, Melissa A Fath and Douglas R Spitz

Journal of oncology, Vol.2009, 519563

2009

DOI: 10.1155/2009/519563

PMCID: PMC2738856

PMID: 19746172

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Abstract

The hypothesis that the Akt inhibitor, perifosine (PER), combined with inhibitors of glutathione (GSH) and thioredoxin (Trx) metabolism will induce cytotoxicity via metabolic oxidative stress in human head and neck cancer (HNSCC) cells was tested. PER induced increases in glutathione disulfide (%GSSG) in FaDu, Cal-27, and SCC-25 HNSCCs as well as causing significant clonogenic cell killing in FaDu and Cal-27, which was suppressed by simultaneous treatment with N-acetylcysteine (NAC). An inhibitor of GSH synthesis, buthionine sulfoximine (BSO), sensitized Cal-27 and SCC-25 cells to PER-induced clonogenic killing as well as decreased total GSH and increased %GSSG. Additionally, inhibition of thioredoxin reductase activity (TrxRed) with auranofin (AUR) was able to induce PER sensitization in SCC-25 cells that were initially refractory to PER. These results support the conclusion that PER induces oxidative stress and clonogenic killing in HNSCC cells that is enhanced with inhibitors of GSH and Trx metabolism.

Details

Title: Subtitle: Inhibition of Glutathione and Thioredoxin Metabolism Enhances Sensitivity to Perifosine in Head and Neck Cancer Cells
Creators: Andrean L Simons - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Arlene D Parsons - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Katherine A Foster - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Kevin P Orcutt - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Melissa A Fath - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Douglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Journal of oncology, Vol.2009, 519563
DOI: 10.1155/2009/519563
PMID: 19746172
PMCID: PMC2738856
NLM abbreviation: J Oncol
ISSN: 1687-8450
eISSN: 1687-8450
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: RO1-CA100045, KO1-CA134941, T32-CA078586-08, R01-CA133114, P30-CA086862
Language: English
Date published: 2009
Academic Unit: Oral Pathology, Radiology and Medicine; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology
Record Identifier: 9984047715802771

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