Ortiz 2013 Abstract SEOR

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Molecular Basis of the radiotherapy-induced mucositis, beneficial effects of melatonin.

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Ortiz F, Escames G, Doerrier C, Venegas C, Lopez LC, Acuna-Castroviejo D, Martinez-unica A, Martinez-Carrillo M, Exposito-Hernandez J (2013)

Event: XVII Congreso Nacional de la Sociedad Española de Oncología Radioterápica

Radiotherapy-induced oral mucositis is one of the main side-effects of this therapy in patients with cancer. The molecular mechanisms of the oral mucositis are currently unknown, thus difficulting the treatment. It was reported that during cell stress, the free radicals produced by the mitochondria are responsible for the NLRP3 inflammasome activation, which in turn yield intracellular changes conducting to pro-inflammatory cytokines activation. During these responses, the NF-kB pathway is also activated, increasing the pro-inflammatory response. The objectives of this study were to analyze the molecular pathways involved in the development of oral mucositis, and to evaluate whether melatonin can prevent this pathology. Materials and methods. Male Wistar rats were subjected to irradiation with a X-ray YXLON Y.Tu 320-D03 irradiator, and the animals received a dose of 7.5 Gy/day for 5 days in their tongues. Rats were treated with 45 mg/day melatonin or vehicle during 21 days post-irradiation, either by local application into their mouths (melatonin gel) or by sc injection. After treatments, rat tongues were obtained for the subsequent determinations. Pharmaceutical preparation of melatonin in gel is currently under patent.

We observe an amelioration of the acute mucosal effects of radiotherapy with topical gel melatonin. Melatonin decreases the expression of NF-kB, iNOS/i-mtNOS, NLRP3, ASC, caspase-1, and proinflammatory cytokines. Melatonin restored mito-chondrial function increasing the activity of the mitochondrial antioxidant enzymes and respiratory chain activity. Electron microscopy also showed tongue’s mitochondria significantly damaged and broken after radiotherapy, which was also prevented by local melatonin gel administration, and we observe a decrease of fibrosis with melatonin.

Considering the low toxicity of melatonin even during long term, which makes possible its clinical use, our results provide evidence for the therapeutic value of melatonin to prevent mucositis in cancer patients.


O2k-Network Lab: ES Granada Acuna-Castroviejo D


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Other 

Organism: Rat 

Preparation: Homogenate, Isolated mitochondria 



HRR: Oxygraph-2k  Event: Oral  radiotherapy, mucositis, melatonin 

Affiliations

1-Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avda. Del Conocimiento s/n, 18100 Armilla, Granada, Spain. 2-Hospital Universitario Virgen de las Nieves, Oncología Radioterápica, Granada, Spain.

Acknowledgements

Supported by grants SAF2009-14037