RESUMO
The aims of the work were to improve our knowledge of the role of H4R in melanoma proliferation and assess in vivo the therapeutic efficacy of histamine, clozapine and JNJ28610244, an H4R agonist, in a preclinical metastatic model of melanoma. Additionally, we aimed to investigate the combinatorial effect of histamine and gamma radiation on the radiobiological response of melanoma cells.Results indicate that 1205Lu metastatic melanoma cells express H4R and that histamine inhibits proliferation, in part through the stimulation of the H4R, and induces cell senescence and melanogenesis. Daily treatment with H4R agonists (1 mg/kg, sc) exhibited a significant in vivo antitumor effect and importantly, compounds reduced metastatic potential, particularly in the group treated with JNJ28610244, the H4R agonist with higher specificity. H4R is expressed in benign and malignant lesions of melanocytic lineage, highlighting the potential clinical use of histamine and H4R agonists. In addition, histamine increased radiosensitivity of melanoma cells in vitro and in vivo. We conclude that stimulation of H4R by specific ligands may represent a novel therapeutic strategy in those tumors that express this receptor. Furthermore, through increasing radiation-induced response, histamine could improve cancer radiotherapy for the treatment of melanoma.
Assuntos
Antineoplásicos/farmacologia , Histamina/farmacologia , Melanoma/metabolismo , Melanoma/patologia , Animais , Antineoplásicos/uso terapêutico , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Terapia Combinada , Modelos Animais de Doenças , Histamina/uso terapêutico , Humanos , Imuno-Histoquímica , Indóis/farmacologia , Melanoma/terapia , Camundongos , Camundongos Nus , Metástase Neoplásica , Estadiamento de Neoplasias , Oximas/farmacologia , Radiação Ionizante , Receptores Histamínicos H4/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The radioprotective potential of histamine on healthy tissue has been previously demonstrated. The aims of this work were to investigate the combinatorial effect of histamine or its receptor ligands and gamma radiation in vitro on the radiobiological response of 2 breast cancer cell lines (MDA-MB-231 and MCF-7), to explore the potential molecular mechanisms of the radiosensitizing action and to evaluate the histamine-induced radiosensitization in vivo in a triple negative breast cancer model. Results indicate that histamine significantly increased the radiosensitivity of MDA-MB-231 and MCF-7 cells. This effect was mimicked by the H1R agonist 2-(3-(trifluoromethyl)phenyl)histamine and the H4R agonists (Clobenpropit and VUF8430) in MDA-MB-231 and MCF-7 cells, respectively. Histamine and its agonists enhanced radiation-induced oxidative DNA damage, DNA double-strand breaks, apoptosis and senescence. These effects were associated with increased production of reactive oxygen species, which correlated with the inhibition of catalase, glutathione peroxidase and superoxide dismutase activities in MDA-MB-231 cells. Histamine was able also to potentiate in vivo the anti-tumoral effect of radiation, increasing the exponential tumor doubling time. We conclude that histamine increased radiation response of breast cancer cells, suggesting that it could be used as a potential adjuvant to enhance the efficacy of radiotherapy.
Assuntos
Neoplasias da Mama/metabolismo , Histamina/metabolismo , Tolerância a Radiação , Radiação Ionizante , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Senescência Celular/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Feminino , Histamina/farmacologia , Humanos , Células MCF-7 , Oxirredução , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The chemical functionalization of cell-surface proteins of human primary fetal bone cells with hydrophilic bioorthogonal intermediates was investigated. Toward this goal, chemical pathways were developed for click reaction-mediated coupling of alkyne derivatives with cellular azido-expressing proteins. The incorporation via a tetraethylene glycol linker of a dipeptide and a reporter biotin allowed the proof of concept for the introduction of cell-specific peptide ligands and allowed us to follow the reaction in living cells. Tuning the conditions of the click reaction resulted in chemical functionalization of living human fetal osteoblasts with excellent cell survival.
Assuntos
Alcinos/química , Química Click , Proteínas de Membrana/química , Osteoblastos/citologia , Membrana Celular/química , Sobrevivência Celular , Células Cultivadas , Feto/citologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Osteoblastos/química , Engenharia Tecidual/métodosRESUMO
Se define y se describe, clínica e histopatológicamente, una enfermedad gingival que hace perder sus tejidos componentes, pudiendo propagarse a zonas vecinas generando cuadros clínicos de mayor gravedad como el Noma. En el caso clínico presentado se observa, además de las lesiones más comunes, la extensión de éstas a través del carrillo, que de no haberse tratado quizás la necrosis lo podría haber perforado. Se comenta el tratamiento realizado, afortunadamente con éxito