Cisplatin and radiation sensitivity in human head and neck squamous carcinomas are independently modulated by glutathione and transcription factor NF-kappaB.
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-kappaB (NF-kappaB), a transcription factor that regulates cytoprotective genes. We have reported that NF-kappaB is constitutively activated in HNSCC, but the relationship of NF-kappaB 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-kappaB 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-kappaB by expression of a degradation-resistant mutant inhibitor-kappaBalpha.


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-kappaB. Expression of a mutant Inhibitor-kappaB after gene transfer inhibited NF-kappaB and sensitized UM-SCC-9 cells to radiation but not cisplatin.


CONCLUSIONS
GSH and transcription factor NF-alphaB 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.
Kato
T
T
Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders National Institute of Health, Bldg. 10, Rm. 5D55, Bethesda, MD 20892, USA.
Duffey
D C
DC
Ondrey
F G
FG
Dong
G
G
Chen
Z
Z
Cook
J A
JA
Mitchell
J B
JB
Van Waes
C
C
D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000503:physiopathology / Q000532:radiotherapy*; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D018076:DNA, Complementary / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010610:Pharyngeal Neoplasms / Q000188:drug therapy* / Q000503:physiopathology / Q000532:radiotherapy*; D016133:Polymerase Chain Reaction; D011829:Radiation Dosage; D011836:Radiation Tolerance; D012016:Reference Values; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D018076:DNA, Complementary; D004273:DNA, Neoplasm; D016328:NF-kappa B; D005978:Glutathione; D002945:Cisplatin