Cisplatin and radiation sensitivity in human head and neck squamous carcinomas are independently modulated by glutathione and transcription factor NF-κB

Background. Response to neoadjuvant cisplatin-based chemotherapy has been used to predict overall response to chemoradiation therapy and to select patients with head and neck squamous cell carcinoma (HNSCC) for organ preservation therapy in NCI and VA cooperative group trials. However, different molecular determinants have been reported to contribute to sensitivity of cells to cisplatin and radiation, including glutathione (GSH), and activation of nuclear factor-κB (NF-κB), a transcription factor that regulates cytoprotective genes. We have reported that NF-κB is constitutively activated in HNSCC, but the relationship of NF-κB to GSH and to cisplatin and radiation sensitivity in HNSCC is unknown. Methods. We examined human HNSCC lines to define the relationship of cisplatin and radiation sensitivity to intracellular GSH and NF-κB and determined whether HNSCC could be sensitized to these modalities by lowering the concentration of glutathione with L-buthionine sulfoximine or inhibiting activation of NF-κB by expression of a degradation-resistant mutant inhibitor-κBα. Results. Cisplatin resistance did not predict radiation resistance in three HNSCC cell lines, UM-SCC-9, 11B, and, 38. Resistance to cisplatin correlated with intracellular GSH, and depletion of GSH by treatment with L-BSO sensitized UM-SCC-9 cells to cisplatin but not radiation. Conversely, radiation resistance was correlated with activation of NF-κB. Expression of a mutant Inhibitor-κB after gene 'transfer inhibited NF-κB and sensitized UM-SCC-9 cells to radiation but not cisplatin. Conclusions. GSH and transcription factor NF-αB can contribute independently to cisplatin and radiation sensitivity of human HNSCC. These results highlight the need to define molecular determinants of chemotherapy and radiation sensitivity for use in the selection of patients and as novel targets for therapy in future chemoradiation therapy trials for organ preservation in patients with HNSCC. (C) 2000 John Wiley and Sons, Inc.