fumarates and Carcinoma--Squamous-Cell

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.. Treatment 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.. This 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.

Topics: Adaptation, Physiological; Apoptosis; bcl-2-Associated X Protein; Buffers; Buthionine Sulfoximine; Carcinoma; Carcinoma, Squamous Cell; Cell Line, Tumor; Dimethyl Fumarate; Fumarates; Glutathione; Head and Neck Neoplasms; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinase 5; Neoplasms, Squamous Cell; Neoplastic Stem Cells; Oxidation-Reduction; Squamous Cell Carcinoma of Head and Neck

Topics: Carcinoma, Squamous Cell; Fumarates; Humans; Male; Middle Aged; Psoriasis; Skin Neoplasms

The inhibitory effect of fumaric acid (FA) on carcinogenesis by potassium 1-methyl-7-[2-(5-nitro-2-furyl)vinyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (trans, NFN) was examined histologically with male ICR/JCL mice. NFN was fed to mice at a dose level of 0.012% in the diet for 14 weeks. These mice were then divided into 2 groups. One group was given a basal diet, and the other group was given a diet containing 1% FA in the subsequent 39 weeks. In the group of 30 mice fed NFN alone, squamous cell carcinomas were found in the stomachs of 7 mice, multiple papillomas in the stomachs of 13 mice, and multiple and large papillary adenocarcinomas in the lungs of 27 animals. The administration of FA suppressed the NFN-induced stomach and lung carcinogenesis. In the group of 32 mice fed NFN and FA, no stomach tumors developed except 1 early-stage of squamous cell carcinoma. In the lungs, only a small focus of mild atypical hyperplasia and a few early-stage adenocarcinomas were noted in 7 and 11 animals, respectively.

Topics: Adenocarcinoma; Animals; Carcinoma, Squamous Cell; Drug Interactions; Fumarates; Lung Neoplasms; Mice; Mice, Inbred ICR; Nalidixic Acid; Papilloma; Stomach Neoplasms