Abstract
BackgroundHead and neck squamous cell carcinoma (HNSCC) is an aggressive and recurrent malignancy owing to intrinsic radioresistance and lack of induction of apoptosis. The major focus of this work was to design a transient glutathione depleting strategy during the course of irradiation of HNSCC in order to overcome their radioresistance associated with redox adaptation.Methodology/Principal FindingsTreatment of SQ20B cells with dimethylfumarate (DMF), a GSH-depleting agent, and L-Buthionine sulfoximine (BSO), an inhibitor of GSH biosynthesis 4 h before a 10 Gy irradiation led to the lowering of the endogenous GSH content to less than 10% of that in control cells and to the triggering of radiation-induced apoptotic cell death. The sequence of biochemical events after GSH depletion and irradiation included ASK-1 followed by JNK activation which resulted in the triggering of the intrinsic apoptotic pathway through Bax translocation to mitochondria.ConclusionsThis transient GSH depletion also triggered radiation-induced cell death in SQ20B stem cells, a key event to overcome locoregional recurrence of HNSCC. Finally, our in vivo data highlight the relevance for further clinical trials of endogenous redox modulation to enhance the cytotoxic effects of radiotherapy.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is among the 10 most common cancers worldwide [1] and, despite new basic and clinical information, the overall 5-year survival rate for HNSCC remains as low as 50% [2]
We previously demonstrated a lack of induction of apoptosis in SQ20B cells, a p53 mutated radioresistant HNSCC cell line following either X-ray [4] or carbon ion irradiation [5]
In order to avoid the cytotoxic effect of drugs, we further examined the effect of a transient pre-treatment of SQ20B cells 4 h before irradiation with 100 mM DMF, 100 mM buthionine sulfoximine (BSO) or in combination (Fig. 1B) which were immediately removed after irradiation by washing with fresh medium
Summary
Head and neck squamous cell carcinoma (HNSCC) is among the 10 most common cancers worldwide [1] and, despite new basic and clinical information, the overall 5-year survival rate for HNSCC remains as low as 50% [2]. We previously demonstrated a lack of induction of apoptosis in SQ20B cells, a p53 mutated radioresistant HNSCC cell line following either X-ray [4] or carbon ion irradiation [5]. After a transient arrest in G2/M phase following exposure to Xrays or more prolonged after carbon ion, some SQ20B cells undergo mitotic catastrophe whereas the majority of them escape mitotic catastrophe and re-enter the cell cycle. The development of adjuvant therapies in order to force the tumour cells to enter apoptosis after irradiation should be a major improvement towards overcoming the HNSCC resistance to anticancer treatments [6]. Head and neck squamous cell carcinoma (HNSCC) is an aggressive and recurrent malignancy owing to intrinsic radioresistance and lack of induction of apoptosis. The major focus of this work was to design a transient glutathione depleting strategy during the course of irradiation of HNSCC in order to overcome their radioresistance associated with redox adaptation
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