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Journal of Oncology
Volume 2009 (2009), Article ID 519563, 10 pages
http://dx.doi.org/10.1155/2009/519563
Research Article

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

Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA

Received 2 March 2009; Accepted 17 June 2009

Academic Editor: Paul Harari

Copyright © 2009 Andrean L. Simons et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.