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

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

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

Author(s) -

Andrean L. Simons,

Arlene D. Parsons,

Katherine A. Foster,

Kevin P. Orcutt,

Melissa A. Fath,

Douglas R. Spitz

Publication year - 2009

Publication title -

journal of oncology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.228

H-Index - 54

eISSN - 1687-8469

pISSN - 1687-8450

DOI - 10.1155/2009/519563

Subject(s) - glutathione , auranofin , buthionine sulfoximine , clonogenic assay , thioredoxin reductase , thioredoxin , oxidative stress , glutathione disulfide , medicine , cancer cell , acetylcysteine , pharmacology , glutathione reductase , cytotoxicity , cancer research , cell , antioxidant , biochemistry , cancer , chemistry , immunology , enzyme , in vitro , rheumatoid arthritis , glutathione peroxidase

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.

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