Combination radiation and chemotherapy are commonly used to treat locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Aggressive dosing of these therapies is significantly hampered by side effects due to normal tissue toxicity. Selenium represents an adjuvant that selectively sensitizes cancer cells to these treatments modalities, potentially by inducing lipid peroxidation (LPO). This study investigated whether one such selenium compound, methylseleninic acid (MSA), induces LPO and radiation sensitivity in HNSCC cells. Results from 4,4-difluoro-4-bora-3a,4a-diaza-S-indacene (BODIPY) C11 oxidation and ferric thiocyanate assays revealed that MSA induced LPO in cells rapidly and persistently. Propidium iodide (PI) exclusion assay found that MSA was more toxic to cancer cells than other related selenium compounds; this toxicity was abrogated by treatment with α-tocopherol, an LPO inhibitor. MSA exhibited no toxicity to normal fibroblasts at similar doses. MSA also sensitized HNSCC cells to radiation as determined by clonogenic assay. Intracellular glutathione in cancer cells was depleted following MSA treatment, and supplementation of the intracellular glutathione pool with N-acetylcysteine sensitized cells to MSA. The addition of MSA to a cell-free solution of glutathione resulted in an increase in oxygen consumption, which was abrogated by catalase, suggesting the formation of H₂O₂. Results from this study identify MSA as an inducer of LPO, and reveal its capability to sensitize HNSCC to radiation. MSA may represent a potent adjuvant to radiation therapy in HNSCC.
Keywords: glutathione; head and neck cancer; lipid peroxidation; methylseleninic acid; radiation; selenium; tocopherol.