RESUMO
Rapamycin has been reported to reduce cancer cell survival in certain tumors following radiation therapy, but the mechanisms driving this phenomenon are unclear. Rapamycin inhibits mTOR signaling, a pathway responsible for several essential cell functions. The objective of this study was to investigate the effects of rapamycin and radiation on the activation and inhibition of mTOR signaling and the relationship between mTOR signaling and DNA damage response in vitro using canine mast cell tumor (MCT) cancer cell lines. Rapamycin rapidly inhibited S6K phosphorylation in a dose-dependent manner. Ionizing radiation (3, 6, or 10 Gy) was able to activate mTOR signalling, but the combination of radiation and rapamycin maintained mTOR inhibition. The comet assay revealed that co-treatment with rapamycin induced modest increases in the severity of DNA damage to MCT cells, but that these differences were not statistically significant. Although the relationship between mTOR and DNA damage response in MCT cancer cell lines remains unclear, our findings suggest the possibility of interaction, leading to enhancement of radiation response.
Il a été rapporté que la rapamycine réduisait la survie des cellules cancéreuses dans certaines tumeurs après une radiothérapie, mais les mécanismes à l'origine de ce phénomène ne sont pas clairs. La rapamycine inhibe la signalisation mTOR, une voie responsable de plusieurs fonctions cellulaires essentielles. L'objectif de cette étude était d'étudier les effets de la rapamycine et des radiations sur l'activation et l'inhibition de la signalisation mTOR et la relation entre la signalisation mTOR et la réponse aux dommages à l'ADN in vitro à l'aide de lignées cellulaires cancéreuses de tumeurs mastocytaires canines (MCT). La rapamycine a rapidement inhibé la phosphorylation de S6K de manière dose-dépendante. Le rayonnement ionisant (3, 6 ou 10 Gy) a pu activer la signalisation mTOR, mais la combinaison de rayonnement et de rapamycine a maintenu l'inhibition de mTOR. Le test des comètes a révélé que le co-traitement avec la rapamycine induisait des augmentations modestes de la gravité des dommages à l'ADN des cellules MCT, mais que ces différences n'étaient pas statistiquement significatives. Bien que la relation entre mTOR et la réponse aux dommages à l'ADN dans les lignées cellulaires cancéreuses MCT reste incertaine, nos résultats suggèrent la possibilité d'une interaction, conduisant à une amélioration de la réponse aux radiations.(Traduit par Docteur Serge Messier).
Assuntos
Doenças do Cão , Mastócitos , Transdução de Sinais , Sirolimo , Serina-Treonina Quinases TOR , Animais , Linhagem Celular Tumoral , Doenças do Cão/tratamento farmacológico , Doenças do Cão/radioterapia , Cães , Mastócitos/efeitos dos fármacos , Mastócitos/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos da radiaçãoRESUMO
Radiation therapy is used to treat cancer by radiation-induced DNA damage. Despite the best efforts to eliminate cancer, some cancer cells survive irradiation, resulting in cancer progression or recurrence. Alteration in DNA damage repair pathways is common in cancers, resulting in modulation of their response to radiation. This article focuses on the recent findings about molecules and pathways that potentially can be targeted to sensitize prostate cancer cells to ionizing radiation, thereby achieving an improved therapeutic outcome.
Assuntos
Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos da radiação , Neoplasias da Próstata/radioterapia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/efeitos da radiação , Aurora Quinases/efeitos da radiação , Ciclo Celular/efeitos da radiação , Quinase 1 do Ponto de Checagem/efeitos da radiação , Quinases Ciclina-Dependentes/efeitos da radiação , Ciclinas/efeitos da radiação , Proteínas de Choque Térmico HSP90/efeitos da radiação , Histona Desacetilases/efeitos da radiação , Humanos , Receptores de Hialuronatos/efeitos da radiação , Subunidade alfa do Fator 1 Induzível por Hipóxia/efeitos da radiação , Masculino , Mutação/efeitos da radiação , Proteína NEDD8/efeitos da radiação , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/radioterapia , Neoplasia Residual , Células-Tronco Neoplásicas/efeitos da radiação , Fosfatidilinositol 3-Quinases/efeitos da radiação , Poli(ADP-Ribose) Polimerases/efeitos da radiação , Proteínas Proto-Oncogênicas c-met/efeitos da radiação , Tolerância a Radiação , Radiação Ionizante , Receptores Androgênicos/efeitos da radiação , Serina-Treonina Quinases TOR/efeitos da radiação , Proteína GLI1 em Dedos de Zinco/efeitos da radiaçãoRESUMO
Head and neck squamous cell carcinoma (HNSCC) is strongly associated with alcohol and tobacco consumption. Lately, the incidence of human papillomavirus (HPV)-related tumors has shown a significant increase, and HPV-related tumors show distinctive features if compared with the HPV-negative counterpart. Locally advanced HNSCC can be treated with concomitant chemoradiotherapy, but early recurrences sometimes occur. Relapses are often related to an intrinsic radioresistance of the tumors. Alterations in intracellular pathways, primarily involved in cell proliferation, apoptosis, and DNA repair, can lead to radioresistance. Preclinical and clinical evidence highlighted that 3 main pathways, including the epidermal growth factor receptor (EGFR), the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and the p53 signaling cascades, play a crucial role in radioresistance development. A future approach may consist in the association of radiotherapy (RT) and selective inhibition of the key pathways involved in radioresistance. Phase I, II, and III clinical trials are currently testing these novel treatment strategies.
