ABSTRACT
Aberration of Notch signaling is one of the key events involved in the development and progression of head and neck squamous cell carcinoma (HNSCC). The Notch pathway controls the tissue-specific differentiation of normal squamous epithelial cells and is frequently altered in squamous carcinomas, thus affecting their proliferation, growth, survival, and chemosensitivity or resistance against anti-cancer agents. In this study, we show that the use of novel, small-molecule inhibitors of Notch signaling, such as FLI-06, can have a beneficial effect on increasing the chemosensitivity of HNSCC to taxane-based chemotherapy. Inhibition of Notch signaling by FLI-06 alone virtually blocks the proliferation and growth of HNSCC cells in both 2D and 3D cultures and the zebrafish model, which is accompanied by down-regulation of key Notch target genes and proteins. Mechanistically, FLI-06 treatment causes cell cycle arrest in the G1-phase and induction of apoptosis in HNSCC, which is accompanied by increased c-JunS63 phosphorylation. Combining FLI-06 with Docetaxel shows a synergistic effect and partially blocks the cell growth of aggressive HNSCC cells via enhanced apoptosis and modification of c-JunS243 phosphorylation via GSK-3ß inhibition. In conclusion, inhibition of Notch signaling in HNSCC cells that retain active Notch signaling significantly supports taxane-based anticancer activities via modulation of both the GSK-3ß and the c-Jun.
Subject(s)
Apoptosis , Cell Proliferation , Head and Neck Neoplasms , Receptors, Notch , Squamous Cell Carcinoma of Head and Neck , Taxoids , Zebrafish , Humans , Animals , Receptors, Notch/metabolism , Receptors, Notch/antagonists & inhibitors , Cell Line, Tumor , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/metabolism , Taxoids/pharmacology , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/metabolism , Cell Proliferation/drug effects , Apoptosis/drug effects , Docetaxel/pharmacology , Signal Transduction/drug effects , Antineoplastic Agents/pharmacology , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/metabolism , Drug Resistance, Neoplasm/drug effects , Drug SynergismABSTRACT
With the increased prevalence of nonalcoholic steatohepatitis (NASH) in the world, effective pharmacotherapy in clinical practice is still lacking. Previous studies have shown that dibenzazepine (DBZ), a Notch inhibitor, could alleviate NASH development in a mouse model. However, low bioavailability, poor water solubility, and extrahepatic side effects restrict its clinical application. To overcome these barriers, we developed a reactive oxygen species (ROS)-sensitive nanoparticle based on the conjugation of bilirubin to poly(ethylene glycol) (PEG) chains, taking into account the overaccumulation of hepatic ROS in the pathologic state of nonalcoholic steatohepatitis (NASH). The PEGylated bilirubin can self-assemble into nanoparticles in an aqueous solution and encapsulate insoluble DBZ into its hydrophobic cavity. DBZ nanoparticles (DBZ Nps) had good stability, rapidly released DBZ in response to H2O2, and effectively scavenged intracellular ROS of hepatocytes. After systemic administration, DBZ Nps could accumulate in the liver of the NASH mice, extend persistence in circulation, and improve the bioavailability of DBZ. Furthermore, DBZ Nps significantly improved glucose intolerance, relieved hepatic lipid accumulation and inflammation, and ameliorated NASH-induced liver fibrosis. Additionally, DBZ Nps had no significant extrahepatic side effects. Taken together, our results highlight the potential of the ROS-sensitive DBZ nanoparticle as a promising therapeutic strategy for NASH.
Subject(s)
Lipogenesis , Liver , Mice, Inbred C57BL , Nanoparticles , Non-alcoholic Fatty Liver Disease , Reactive Oxygen Species , Animals , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , Reactive Oxygen Species/metabolism , Mice , Nanoparticles/chemistry , Lipogenesis/drug effects , Male , Liver/metabolism , Liver/drug effects , Liver/pathology , Receptors, Notch/metabolism , Receptors, Notch/antagonists & inhibitors , Humans , Inflammation/drug therapy , Inflammation/metabolism , Bilirubin , Polyethylene Glycols/chemistry , Disease Models, Animal , Hepatocytes/metabolism , Hepatocytes/drug effects , DibenzazepinesABSTRACT
La vía de Notch regula procesos importantes en el riñón implicados en el desarrollo embrionario y en situaciones de agresión tisular. Así, en una gran variedad de nefropatías crónicas humanas se ha descrito una activación local de este sistema, sugiriendo que algunos de sus componentes podrían ser biomarcadores de daño renal. Los estudios realizados en modelos experimentales, modulando genéticamente componentes de la vía Notch o mediante su bloqueo farmacológico con inhibidores de la γ-secretasa, han demostrado la participación de esta vía en la regeneración renal, en la apoptosis de podocitos, en la proliferación y activación de fibroblastos y en la transición epitelio-mesenquimal de las células tubuloepiteliales. Estudios recientes sugieren una interacción entre las vías Notch y NF-κB, la cual podría jugar un papel relevante en el proceso inflamatorio renal. Por otra parte, en los últimos años se han descrito miRNA que son capaces de regular componentes de la vía Notch y modular sus respuestas. Todos estos datos indican que el bloqueo de la vía de señalización Notch podría representar una nueva opción terapéutica para la enfermedad renal
Notch pathway regulates key processes in the kidney, involved in embryonic development and tissue damage. In many human chronic renal diseases a local activation of Notch pathway has been described, suggesting that several components of Notch pathway could be considered as biomarkers of renal damage. Experimental studies by genetic modulation of Notch components or pharmacological approaches by γ-secretase inhibitors have demonstrated the role of this pathway in renal regeneration renal, podocyte apoptosis, proliferation and fibroblasts activation, and induction of epithelial to mesenchymal transition of tubular epithelial cells. Recent studies suggest an interaction between Notch and NF-κB pathway involved in the regulation of renal inflammatory process. On the other hand, there are some miRNAs that could regulate Notch components and down-stream responses. All these data suggest that Notch blockade could be a novel therapeutic option for renal diseases
Subject(s)
Humans , Receptors, Notch/metabolism , Renal Insufficiency, Chronic/therapy , Receptors, Notch/antagonists & inhibitors , Signal Transduction , Growth Differentiation Factors/metabolism , Angiotensin II/metabolism , NF-kappa B/metabolism , RNA, Long Noncoding/metabolismABSTRACT
La vía de señalización Notch desempeña un papel fundamental en las diferentes etapas del desarrollo celular como la proliferación, crecimiento, diferenciación y apoptosis. Estudios recientes han demostrado que, dependiendo del nivel de expresión y del contexto celular, los receptores de membrana Notch contribuyen en la resistencia a apoptosis en células tumorales. Estos descubrimientos sugieren que componentes de la vía de señalización Notch son un blanco potencial para el desarrollo de terapias más efectivas contra el cáncer. Esta revisión describe la función de la vía Notch y nuevas estrategias utilizadas en la modulación de su señal.